Clinical Immunology 203 (2019) 81–121

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Clinical Immunology
journal homepage: www.elsevier.com/locate/yclim

Review Article

Sjogren’s syndrome: An update on disease pathogenesis, clinical T

manifestations and treatment
⁎
Frederick Vivinoa, , Vatinee Y. Bunyab, Giacomina Massaro-Giordanob, Chadwick R. Johra,
Stephanie L. Giattinoa, Annemarie Schorpiona, Brian Shaferb, Ammon Peckc, Kathy Sivilsd,
⁎
Astrid Rasmussend, John A. Chiorinie, Jing Hef, Julian L. Ambrus Jrg,
a
Penn Sjögren's Center, Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 3737 Market Street, Philadelphia, PA 19104, USA
b
Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, 51 N. 39th Street, Philadelphia, PA 19104, USA
c
Department of Infectious Diseases and Immunology, University of Florida College of Veterinary Medicine, PO Box 100125, Gainesville, FL 32610, USA
d
Oklahoma Medical Research Foundation, Arthritis and Clinical Immunology Program, 825 NE 13th Street, OK 73104, USA
e
NIH, Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, Building 10, Room 1n113, 10 Center DR Msc 1190, Bethesda, MD
20892-1190, USA
f
Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China
g
Division of Allergy, Immunology and Rheumatology, SUNY at Buffalo School of Medicine, 100 High Street, Buffalo, NY 14203, USA

1. Introduction/History and lacrimal glands [4,11]. The syndrome is named, however, after an
Ophthalmologist from Jonkoping, Sweden, Dr Henrik Sjogren, who in
Sjogren’s syndrome (SS) is one of the most common autoimmune 1930 noted a patient with low secretions from the salivary and lacrimal
diseases. It may exist as either a primary syndrome or as a secondary glands. He subsequently published on a series of patients with “kera-
syndrome when associated with other autoimmune diseases, such as toconjunctivitis sicca” in 1933 and 1951 that brought the syndrome to
rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis worldwide medical attention [11,12]. He distinguished the primary
and primary biliary cirrhosis [1–4]. The true prevalence of SS is very disease from other causes of keratoconjunctivitis sicca, such as vitamin
hard to determine because of frequent changes in diagnostic criteria, A deficiency and tuberculosis. In the 1950’s and 1960’s Sjogren’s syn-
variation in the method of diagnosis based on the training of the clin- drome was felt to be a relatively rare disorder and the appreciation of
ician making the diagnosis (i.e. Ophthalmologist vs. Oral surgeon v its association with other autoimmune diseases was just starting [13].
Rheumatologist vs. Internist, etc.) and inclusion of novel diagnostic In the 1970’s, immunological abnormalities associated with Sjogren’s
markers that are potentially more sensitive. While SS was once con- syndrome, especially hypergammaglobulinemia, monoclonal gammo-
sidered a rare disease, it is now considered the second most common pathiy and various lymphoid abnormalities were just being elucidated.
autoimmune disease, after rheumatoid arthritis. Its prevalence is esti- The association between SS and lymphomas was noted, minor salivary
mated at 1% (0.1 – 4.8%) with an incidence of 7 per 100,000 in the gland biopsies were used for diagnosis, immunological therapies, such
United States. It is felt that roughly 4 million Americans have SS with as the use of corticosteroids were attempted, the association of SS with
90% of them being women and 50% of them having SS in association HLA-B8 and DR3 was made, and animal models for SS were first ex-
with another autoimmune disease [5–7]. The incidence of SS is felt to amined [14–16]. In the 1980’s came the association of SS with anti-SSA
be lower in China and higher in Japan [8]. While SS is felt to be a and anti-SSB antibodies [17]. In addition, SS was noted to have a strong
disease predominantly of women, with a female to male ration of 9:1, correlation with chronic fatigue, cholinergic agents were used to in-
the incidence of SS is likely higher in males than is currently estimated, crease salivary gland flow [18], immunological studies focused on the
since males tend to make a different pattern of autoantibodies than hypothesis that SS involves abnormal B cells and T cells of the adaptive
females and are often missed with the current diagnostic criteria [9,10]. immune system producing autoreactive antibodies and direct cyto-
Dr Johann von Mikulicz-Rdeck, a surgeon from Cernowitz, Austria, toxicity [19], and genetic studies identified particular human leukocyte
is credited with identifying the first patient with Sjogren’s syndrome in antigen (HLA) associations with SS [20]. The 21st century has seen a
1892 based on round-cell infiltrate and acinar atrophy of the parotid blossoming of research in SS that has led to improved understanding of

⁎
Corresponding author.
E-mail addresses: frederick.vivino@uphs.upenn.edu (F. Vivino), vatinee.bunya@uphs.upenn.edu (V.Y. Bunya),
Giacomina.Massaro-Giordano@uphs.upenn.edu (G. Massaro-Giordano), Chadwick.Johr@pennmedicine.upenn.edu (C.R. Johr),
Stephanie.Giattino@uphs.upenn.edu (S.L. Giattino), annemarie.schorpion@uphs.upenn.edu (A. Schorpion), Brian.Shafer@pennmedicine.upenn.edu (B. Shafer),
peck@ufl.edu (A. Peck), sivilsk@omrf.org (K. Sivils), Astrid-Rasmussen@omrf.org (A. Rasmussen), jchiorini@dir.nidcr.nih.gov (J.A. Chiorini),
jambrus@buffalo.edu (J.L. Ambrus).

https://doi.org/10.1016/j.clim.2019.04.009
Received 19 April 2019; Accepted 19 April 2019
1521-6616/ © 2019 Published by Elsevier Inc.
F. Vivino, et al. Clinical Immunology 203 (2019) 81–121

clinical manifestations, greater appreciation of disease pathophysiology submandibular glands may be unilateral or bilateral and observed in up
including the involvement of the innate immune system, role of epi- to 30% of SS patients. This swelling can be the presenting manifestation
thelial cells and other cell types, determination of contributory genetic of the disease or occur at any point during the course. Patients who
factors, development of improved animal models and therapeutic trials present with acute glandular swelling associated with fevers and facial
with encouraging outcomes. These are discussed in the remainder of erythema are presumed to have acute bacterial sialadenitis until proven
this review. otherwise. An attempt should be made to milk the involved gland and
culture the exudate from Stenson's or Wharton's duct. An individual
2. Clinical manifestations who develops salivary gland swelling after eating or chewing most
likely has obstructive symptoms due to sialolithiasis or sialostenosis
2.1. Oral manifestations and complications with mucus plugs. When the swelling begins to subside patients may be
aware of passing stones or gravel in the mouth or experiencing a sour
2.1.1. Dry mouth taste from a mucus plug. Intermittent or persistent salivary gland
Sjögren's is often referred to as the "sicca syndrome" (from the Latin swelling may also be due to inflammatory sialadenitis from lympho-
siccus meaning dry or thirsty) and xerostomia is one of its most pre- cytic infiltration of the major salivary glands and is typically responsive
valent symptoms. to steroids and other immunosuppressives. Sjögren's patients on chronic
Saliva is a chemically complex fluid containing over 2000 proteins or frequent intermittent corticosteroids or with metabolic disorders
and various glycoproteins, lipids, electrolytes, small molecules, specific sometimes develop sialadenosis or fatty infiltration of the glands. Any
salivary IgA’s, hormones and buffers that all play a vital role in oral individual with persistent glandular swelling despite prolonged therapy
health [21]. It preserves the dentition and inhibits the growth of mi- (e.g. > 12 weeks) or whose salivary glands feel indurated or nodular
croorganisms; lubricates and protects the tongue and oral mucosa from should undergo imaging and/or a major salivary gland biopsy to rule
trauma; facilitates taste, mastication, deglutition, speech and initiates out non-Hodgkin’s B-cell lymphoma.
carbohydrate digestion in the mouth [22,23]. Consequently, the oral
signs and symptoms of SS extend far beyond those of simple dryness. 2.2. Spectrum of ocular disease
Patients may initially notice intermittent daily or nocturnal dryness
or cotton mouth sensation that gradually becomes more prominent Dry eye, or keratoconjunctivitis sicca (KCS) is the most common
during the day. As the condition progresses Sjögren's sufferers even- ocular manifestation of SS [30]. As such, management of Sjögren's is
tually find themselves constantly drinking water. The mucosa becomes heavily focused on ocular surface rehabilitation. However, SS can also
traumatized and mouth sores and/or oral discomfort develop. This may lead to other serious vision-threatening ocular complications including
eventually lead to glossodynia or stomatopyrosis. The patient may de- corneal melts [31], uveitis [32], scleritis [33], and optic neuritis
scribe an unpleasant taste in the mouth or dysgeusia with familiar [34,35] as detailed below.
foods. Food particles may stick to the gums and mucosa and, it may be
difficult to chew and swallow dry foods without water. Eating becomes 2.2.1. Tear film
unpleasant and weight loss ensues. Cheilosis is present. Dry throat, The tear film is critical for maintaining the health of the ocular
hoarseness and dysphonia can also occur. The dryness may also pro- surface. It coats the cornea and conjunctiva and serves to maintain
gress to the point of disturbing sleep due to nocturnal fluid ingestion optical clarity, prevent bacterial overgrowth, prevent epithelial break-
and nocturia. The lack of saliva may also cause downstream con- down, and serves as a barrier against environmental hazards [36]. The
sequences in the gastrointestinal tract as described below [24]. tear film consists of three main components: the aqueous layer, lipid
layer, and mucin layer [36]. The aqueous layer comprises the largest
2.1.1.1. Caries. Carious, chipped and broken teeth are among the most component and is produced by both the primary lacrimal gland and
visible and costly dental complications of SS [25,26]. Like other accessory lacrimal glands. The meibomian glands located in both the
xerostomic populations, Sjögren's sufferers frequently develop cavities upper and lower eyelids produce the outer lipid layer, which stabilizes
in unusual locations including: root caries at or below the gingival the tear film and limits the evaporation of tears. Finally, the mucin
margin, cervical caries in the neck of the tooth and cavities on the layer is secreted by the corneal and conjunctival epithelium, as well as
incisal surfaces [27]. Cervical lesions that extend circumferentially goblet cells within the conjunctival epithelium and helps tears adhere
around the tooth neck eventually cause the tooth to fracture. to the ocular surface. The mucin layer is a glycocalyx formed primarily
Restorative work tends to be less successful in SS patients than other by high molecular weight glycosylated membrane-associated mucins
groups and many patients will eventually require partial or complete such as MUC1, MUC4, and MUC16 [37]. These mucins interact with
dentures. Unfortunately, this solution often fails to solve the problem galectin-3, an important signaling protein that helps prevent pathogen
since denture adhesion will be less than optimal without sufficient entry into the eye; mucins also decrease friction of the ocular surface
saliva [23]. during blinking [37]. Abnormalities in the any of these three layers can
lead to an unstable tear film and dry eye disease.
2.1.1.2. Chronic erythematous candidiasis. The normal oral microbiota
for most individuals includes Candida albicans and other Candida 2.2.2. Mechanism of dry eye
species [28,29]. Certain conditions or circumstances such as diabetes, A comprehensive assessment by a skilled eye care provider is ne-
antibiotic or steroid use, or xerostomia may predispose to Candida cessary to determine the primary cause(s) of dry eye. SS has classically
overgrowth and pathogenicity. Patients typically complain of been associated with aqueous tear deficient dry eye [30] but there is
stomatopyrosis or intolerance of acidic or spicy foods. Findings may evidence that meibomian gland dysfunction (MGD) also plays a role
include angular cheilitis, atrophy of the filiform papillae and mucosal [38]. Sjögren's can cause destruction of both the primary and secondary
erythema. In chronic cases the tongue may also develop an lacrimal glands via T cell-mediated inflammation [30] with resultant
erythematous, cobblestoned appearance. The classic findings of hyposecretion of tears. Decreased tear production can easily be de-
pseudomembranous candidiasis occur less frequently. The overgrowth tected on clinical exam using the Schirmer test. A result of less than
of Candida may further contribute to the patient’s lack of pleasure from 10mm/ 5 min. indicates decreased tear production [39]. Vital dyes such
eating and poor oral intake. as fluorescein and lissamine green are also used to assess the severity of
ocular surface damage.
2.1.2. Major salivary gland swelling With MGD, there is decreased expression of the lipid layer onto the
Acute, intermittent or chronic persistent swelling of the parotid or ocular surface with resultant tear film instability and evaporative dry

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eye. This can be detected on clinical examination by inspection of the clinician, they may leave a residual epithelial defect that becomes a
eyelids with biomicroscopy, direct visualization of the meibomian potential nidus for infection. Additionally, removal of the filaments
glands using infrared imaging (meibography) or by performance of a only provides temporary relief as recurrence is frequently observed. N-
fluorescein tear film break up time (TBUT) [38]. In this test, following acetylcysteine eye drops may be used to help break down filaments in
the instillation of fluorescein into the eye, the patient blinks once, then conjunction with aggressive surface lubrication or use of a bandage
holds the eye open while the number of seconds is counted until the contact lens [40]. When this problem becomes chronic, filaments can
fluorescein starts to disappear. A value greater than 10 seconds is fuse into large mucous plaques that may be recalcitrant to conventional
normal and the lower the value on TBUT the more severe the eva- therapies [40].
porative dry eye [38]. Because of the abnormal tear film in patients with SS, special con-
siderations must be made when considering manipulation of the ocular
2.2.3. Dry eye signs and symptoms surface. Notably, there have been many reports of sterile corneal melts
Among patients with SS, dry eye is one of the most prominent that may lead to perforation following routine cataract, corneal, and
clinical features [40,41]. Other common symptoms include a burning refractive surgeries in SS [47–49]. Therefore, treatment of KCS must be
sensation, grittiness, itching, redness, mucus exudate, photophobia and optimized before consideration of such procedures. Contact lenses
glare [42]. Symptoms often worsen throughout the day, and patients should also be used with caution in SS as patients are at higher risk for
experience transient episodes of blurred vision that improve with worsening dryness or bacterial or fungal keratitis due to the irregular
blinking or resting the eyes. Conditions that exacerbate evaporation nature of the ocular surface [50].
from the eye such as air conditioning, heaters, low humidity, or wind
will further worsen KCS. Additionally, activities that require con- 2.2.6. Ocular morbidities beyond dry eye
centration such as reading, watching TV, or using the computer may In addition to KCS, SS can also cause a myriad of ophthalmic
also aggravate symptoms due to decreased blinking and increased complications. SS has been associated with both anterior and posterior
evaporation from the ocular surface [39]. In its earliest stages, KCS may uveitis both of which may present with pain, photophobia, floaters, and
cause mild discomfort. However, as the disease progresses it may cause decreased vision [32,51]. Additionally, anterior uveitis and scleritis
severe pain, damage to the ocular surface, and chronic visual impair- [33] both cause ocular redness in patients with primary SS. Scleritis
ment. As a result, KCS can significantly impact activities of daily living must be diagnosed in a timely and accurate manner since failure to
as well as work productivity, and as such, many patients report a re- promptly treat may lead to scleral perforation, a sight and globe-
duced quality of life [42]. Patients with concomitant MGD (posterior threatening complication. Demyelinating conditions such as optic
blepharitis) may experience increased burning, itchiness and foreign neuritis and neuromyelitis optica (NMO) have also been associated with
body sensation of the eyes along with redness, swelling and/or crusting SS [34,35,51]. In optic neuritis, patients complain of decreased vision,
and of the eyelids [39]. Occasionally, Sjögren's KCS may also be mis- decreased color saturation, and pain with eye movement. These
diagnosed as allergic conjunctivitis because of itchiness and other symptoms require aggressive treatment with high dose oral or in-
overlapping symptoms [43]. travenous steroids [51]. NMO is a more severe condition characterized
by optic neuritis in association with longitudinally extensive transverse
2.2.4. Corneal neuropathy myelitis and is even more challenging to treat [51,52].
Although the clinical signs of dry eye may be similar between SS In conclusion, SS causes dry eye secondary to the autoimmune de-
and non-SS dry eye patients, individuals with SS often complain of more struction of the lacrimal glands leading to aqueous deficient dry eye,
severe symptoms such as burning, chronic pain and photo allodynia which is commonly exacerbated by concomitant meibomian gland
[44]. This phenomenon may be due in part to the presence of a corneal dysfunction. Dry eyes can predispose the ocular surface to vision-
neuropathy [45]. In patients with SS, corneal nerves exhibit altered threatening complications such as corneal melting, ulcers, and per-
corneal morphology (e.g. tortuosity, decreased density, abnormal forations. Regular vigilance for other ophthalmic manifestations of SS
branching) and increased dendritic cell density that can be detected such as uveitis, scleritis, and optic neuritis is equally important.
with in vivo confocal microscopy [44,45]. Regardless of the etiology of
the corneal neuropathy, the change in morphology is associated with an 2.2.7. Other sicca symptoms
increase in symptoms. Even in the absence of clear signs of dry eye on Since exocrine glands exist throughout the body other xeroses and/
slit lamp exam, many patients will experience a phenomenon known as or complications thereof may include xeroderma, chronic pruritus,
“pain without stain” [46]. When symptoms exist in the absence of xeromycteria, epistaxis, dry ears, itchy ears, xerotrachea, cough, vagi-
clinical signs such as ocular surface staining, further testing with con- nitis sicca and dyspareunia. The latter symptoms may lead to sexual
focal microscopy is indicated [44,45]. dysfunction, decreased activity and decreased sexual satisfaction in SS
[53].
2.2.5. Complications of KCS As observed with the eyes and mouth, decreased moisture of other
Untreated, dry eye disease can be extremely detrimental. The tear mucosal surfaces in Sjögren's may also predispose to infections in these
film is responsible for a significant portion of the refractive power of the areas as well.
eye, and as such an irregular tear film will distort the patient's vision
[42]. In addition, desiccation of the ocular surface can lead to epithelial 2.3. Systemic manifestations
breakdown. Without a healthy tear film or corneal epithelium, the eye
is also at risk for the development of bacterial and fungal infections that 2.3.1. Fatigue and other constitutional symptoms
can lead to corneal ulcers. Due to the severe inflammation on the ocular Fatigue is the most common symptom in SS after dry eye and dry
surface in patients with KCS, sterile, or non-infectious, corneal ulcers mouth, occurring in ~70-80% of patients [54–56]. Though it is
may also form. These ulcers can lead to corneal melting and, in severe common, it is poorly understood [57]. The pathogenesis is unknown
cases, perforation [31], and endophthalmitis. and research thus far suggests that it is something intrinsic to SS
Another disabling complication of moderate-severe dry eye disease without a clear etiology [54,55,57,58]. Though that may be true for SS
is filamentary keratitis. In this condition strands of mucus and protei- in general, for any given patient with SS, the cause of fatigue may be
naceous debris from shed epithelial cells remain attached to the corneal multifactorial with potential contributors including poor sleep (owing
surface [40]. With each blink, the filaments are disturbed and cause to sleep apnea, restless legs, frequent awakening due to pain, and/or
severe pain, foreign body sensation, photophobia, and decreased vision. nocturia), depression, anxiety, fibromyalgia, anemia, hypothyroidism,
When filaments are removed either spontaneously or intentionally by a dry mouth, and other reasons.

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As the cause of fatigue in SS is unknown, it is perhaps not surprising occur from inflammatory myopathy. The frequency of inflammatory
that its management is often challenging with underwhelming results. myositis in SS is quite rare and felt to occur in < 2% [62,69,76]. It is
Fatigue in SS tends to persist over time. One prospective study showed often subclinical or mild compared to polymyositis and dermatomyo-
that it did not change significantly over a 5-year period [54]. One co- sitis and presents in a nonspecific fashion, sometimes with mild
hort study of 160 SS patients showed by multivariate analysis that weakness, myalgias, or no symptoms at all and, typically, with lower
depression, fibromyalgia, and the personality trait of neuroticism were elevation in creatine kinase than that observed in these other disorders
all independent contributors to fatigue in SS and the authors thus re- [75].
commend collaboration with behavioral health specialists to treat this
problem [58]. Though studies have shown that cytokines and other 2.3.3. Hematologic abnormalities
markers of inflammation are not associated with fatigue in SS [57], one The hematologic manifestations of SS can be separated into cellular
small double-blind, placebo-controlled, randomized pilot study de- and humoral components. The main cellular abnormalities, cytopenias,
monstrated modest efficacy of rituximab in reducing fatigue [59]. although more closely associated with systemic lupus erythematosus
However, given its high financial cost, potential side effects, and lack of (SLE) are quite common in SS and can even be the presenting feature
strong evidence, rituximab is not recommended for fatigue in SS [77,78]. Humoral manifestations include hypergammaglobulinemia,
treatment guidelines [60,61]. hypogammaglobulinemia, monoclonal gammopathy, cryoglobuli-
Fevers may also be a prominent manifestation of SS and, in most nemia, and elevations in autoantibodies. Although the hematologic
large cohorts, occur in 6-13% of patients [62–64] at the time of initial manifestations found in SS are typically mild and clinically silent,
evaluation. They may be low grade and inconsequential or sometimes several are prognostic markers for the development of lymphoma and
more severe and associated with other constitutional symptoms in- increased disease mortality [62,69,79–82].
cluding malaise, asthenia, worsening fatigue or a flu-like illness. Fevers
in SS can be the presenting manifestation of the disease [62,65] or 2.3.4. Anemia
occur later in the course [62,63]. Persistent fevers associated with Cytopenias are found in 30-60% of SS patients, with bi-cytopenias in
weight loss and/or night sweats should always prompt evaluation for an 5-10%, and pancytopenia in only 1% [66,69,79,83]. The anemia of
occult lymphoma. chronic inflammation most commonly occurs and is found in about 15-
45% of patients depending on the series and definition of anemia
2.3.2. Musculoskeletal manifestations [62,68,69,79]. Typically, it is mild and with no identifiable cause
As with fatigue, articular manifestations are very common in SS outside of the SS itself [79]. Other forms such as hemolytic anemia
with arthralgias occurring in ~50 to 75% [62,66,67] and arthritis (1%), aplastic, pernicious, myelodysplastic, and pure red cell aplasia
(synovial inflammation) in ~10-30% [62,66–69]. The most common have also been reported in SS but rarely occur [69,79]. One Spanish
pattern observed is polyarticular and symmetric although monoarthritis series of 380 consecutive patients with primary Sjögren’s syndrome
has been observed. Signs and symptoms mainly involve the PIP, MCP, (pSS) noted that 93% of anemias were normochromic and normocytic
and wrist joints though other joints can be involved as well [67,68,70]. with only 4% microcytic and 3% macrocytic [79]. Severe anemia (de-
The onset of articular manifestations in SS is variable. One study of 419 fined by a hemoglobin level < 9 mg/dL) was infrequent and, found in
SS patients followed for a mean of 76 months reported that joint only 4% of pSS patients [79]. It is important to note that anemia can
symptoms started before sicca symptoms in ~20%, simultaneously in also develop as a late complication of the disease. This was demon-
~50%, and after sicca in ~30% [67]. strated in a Greek series of 536 pSS patients followed for a median of 31
For any given SS patient with arthritis, it may be difficult to de- mo. [69]. At the time of diagnosis 28.5% of subjects had anemia while
termine whether the arthritis is due to SS alone or to concurrent another 16.4% developed it during the follow-up period [69]. Anemia
rheumatoid arthritis (RA) since both have the same pattern of joint in SS has been associated with a positive ANA (86% vs 70%), positive
involvement. The inflammatory arthritis of Sjögren's however is, in SSA/SSB (OR 2.6, 95% CI 1.5 - 4.4), higher focus scores on lip biopsies,
most cases, nonerosive. An elevation in rheumatoid factor (RF) testing and with peripheral neuropathy (22% vs 4%, p = 0.001) [68,69].
is characteristic of RA and is present in ~75% of RA cases; however, it
is also present in ~60-70% of SS cases and is therefore not helpful in 2.3.5. Leukopenia
distinguishing one disease from the other [71]. Anti-cyclic citrullinated Leukopenia has been observed in 10 to 25% of patients with SS
protein antibodies (ACPA), on the other hand, are elevated in a similar [62,69,79,83]. One series reported that more cases were related to the
percentage of RA patients but in only ~10-15% of SS patients and effect of drugs or toxins than the disease itself [69]. Leukopenia in pSS
therefore may be useful in predicting the development of RA in those is predominantly mild with only 0.2% of all patients having a white
with SS [71]. They do not, however, permit the differentiation of one blood cell count less than 2000 cell/mm3 [79].
disorder from the other as one cohort study showed that among 16 SS When considering the white blood cell differential in SS, neu-
patients with +ACPA, almost half developed RA after a median follow tropenia is noted in roughly 5 to 30% [69,79,83,84], lymphopenia in
up period of 8 years [71]. about 10% [69,79,83], and eosinophilia in 12% [79]. Neutropenia is
For any given SS patient with arthralgias, it may be difficult to associated with an increase in hospital admissions due to infections
distinguish between pain due to SS alone or pain due to concurrent (24% vs 9%, p = 0.002), especially in those with a neutrophil count
fibromyalgia as both have many overlapping features. Fibromyalgia is a less than 1000/mm3 as noted in one Spanish series of 300 pSS patients
syndrome characterized by chronic widespread musculoskeletal pain, [84]. Severe neutropenia, as defined by a neutrophil count of less than
chronic fatigue, disturbed sleep, and myriad somatic symptoms that is 500/mm3, is quite rare, found in only 2% of patients in the same series
felt to be associated with dysregulation of pain processing in the central [84]. The presence of neutropenia in SS patients has been associated
nervous system. Though its prevalence in the general population is only with the development of lymphoma [69] as has the presence of CD4+
~2%, fibromyalgia has been noted in ~10-30% of patients with SS T-cell lymphopenia [82]. Other statistically significant hematologic
[55,72–74]. In SS patients with concurrent fibromyalgia, medications associations in SS include the following: neutropenia with positive SSA/
such as duloxetine or pregabalin may be preferred over im- B (53% vs 22%), neutropenia with low C4 (17% vs 8%) [84], leuko-
munosuppressive medications to treat joint pain. penia with positive SSA and RF [68,79], and lymphopenia with renal
In addition to the joints, the muscles can also be affected in SS. Up to involvement (13% vs 3%) [79].
70% of SS patients may complain of myalgias [75]. Weakness can occur
from hypokalemia as a result of renal tubular acidosis as noted in the 2.3.6. Thrombocytopenia
renal manifestations section of this chapter. Weakness in SS can also Thrombocytopenia is noted in 5 to 13% of SS patients

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[62,68,69,83]. As with anemia and leukopenia, it is usually mild [79]. 2.3.9. Antiphospholipid antibodies
Moderate thrombocytopenia (< 100 K/mm3) is found in 3% of SS pa- In SLE high levels of anti-phospholipid antibodies (aPL) are asso-
tients and severe thrombocytopenia (< 50 K/mm3) in only 0.4% [79]. ciated with an increased risk of fetal loss and venous and arterial
Interestingly, a Chinese series of 131 consecutive hospital admissions thrombosis. Abnormal aPL results has also been found in 13-38% of SS
for severe thrombocytopenia (platelet count < 20 K/mm3) found that patients, though mostly at low to moderate titers. These aPLs were
of those due to an underlying connective tissue disease, the most associated mainly with hypergammaglobulinemia but not with throm-
common was pSS (53.7% of thrombocytopenia cases) followed by SLE bosis or fetal loss [79,89]. This suggests that the presence of low to
(40.5%) [85]. Thrombocytopenia in SS has been shown to have statis- moderate titer aPLs seen in SS may simply occur as an epiphenomenon
tically significant associations with renal disease (15% vs 5%), positive of polyclonal B cell activation [89].
SSB (40% vs 25%), and positive minor salivary gland biopsy (OR 4.6,
95% CI 1.2 - 39.7) [68]. It is postulated that the etiology of thrombo- 2.3.10. Hypocomplementemia
cytopenia in SS is due to anti-platelet antibodies and or immune com- In addition to immunoglobulins, the other humoral component to
plex mediated destruction [82]. consider in SS is complement. Low levels of C3 are reported in about
10-15% [66,68,69,83] of SS patients and low levels of C4 in about 5-
20% [62,66,68,69,83]. In some cases, this may reflect disease activity
2.3.7. Hyper- and Hypogammaglobulinemia related to consumption of complement from immune complex forma-
SS is characterized by lymphocytic infiltration of involved organs tion. Low C4 levels have been found to be associated with higher focus
and polyclonal B-cell hyperactivity. This is reflected by some of the scores on minor salivary gland biopsy [68] and lymphomas [69]. In
humoral abnormalities found in SS such as hypergammaglobulinemia addition, similar to hypergammaglobulinemia, hypocomplementemia
which may occur in about 20-50% of patients [62,68,69,79]. Not sur- has been found to help predict the diagnosis the SS. As mentioned
prisingly, hypergammaglobulinemia also correlates with higher focus above, among 830 subjects who met some but not all of the 2002 AECG
scores on salivary gland biopsies [68]. Interestingly, hypergammaglo- classification criteria for SS, those with hypocomplementemia at study
bulinemia is one of two lab tests that have been shown to be predictive entry were 6 times more likely to meet AECG classification criteria
of the development of SS in those in whom the diagnosis is suspected upon follow-up 2-3 years later than in those with normal im-
[86]. This was demonstrated in a group of 830 subjects who did not munoglobulin levels (1.8-20.4, p = 0.0004) [86].
meet 2002 American European Consensus Group (AECG) classification
criteria for SS but in whom some objective findings of SS were present 2.3.11. Lymphoma
(e.g. Schirmer test of < 5mm/5 min.). Those with hypergammaglobu- As Sjögren’s syndrome is a disease characterized by B-cell hyper-
linemia at study entry were 4 times more likely to meet AECG classi- activation, it is not surprising that those with SS have an increased risk
fication criteria upon follow-up 2-3 years later than those with normal of developing non-Hodgkin's B-cell lymphoma. The relative risk had
immunoglobulin levels (95% CI 1.5 - 10.1, p = 0.006) [86]. Hy- been estimated to be 15-20 times that of the general population
pergammaglobulinemia is also associated with an increase in the ery- [90–92] but more recent studies suggest that this may be an over-
throcyte sedimentation rate (ESR) as seen in about 20% of SS patients estimation [90,93–97]. The pathogenesis has been recently reviewed
[79]. Severe ESR elevations with levels greater than 100 mm/hr. are [90]. The most common type of lymphoma found in SS is a low-grade B-
rare and found in only 4% of SS patients [79]. Though elevated im- cell non-Hodgkin lymphoma (NHL) of the marginal zone histologic
munoglobulin levels are not unexpected in SS, hypogammaglobuli- type, especially those of mucosa-associated lymphoid tissue (MALT)
nemia has been noted in about 5- 15% [69,79]. In one series this finding [90]. Other, less common subtypes include lympho-plasmacytoid lym-
was observed in 4 of 8 SS patients who developed lymphoma [79]. In phoma and, diffuse large B-cell lymphoma which is more aggressive
the same series, immunodeficiencies were rare, found in only about 1% and sometimes develops as a transformation from a low-grade subtype
of SS patients (CVID in 2 and IgA deficiency in 1) [79]. [90].
The lifetime risk of developing NHL in SS is felt to accumulate with
time and has been estimated at 5-10% [90,93,98]. It tends to occur
2.3.8. Monoclonal gammopathy wherever the SS happens to be active which is most commonly in the
Monoclonal immunoglobulins have been observed in about 10- 20% parotid and submandibular glands but can also be in the lymph nodes,
of patients [79,80,83]. IgG is the most common isotype followed by IgM orbits, nasopharynx, stomach, thyroid, and lungs [90]. The course tends
[80]. IgA and free light chains have also been reported [80]. Many of to be indolent with a small tumor burden, normal LDH, and without B-
the monoclonal immunoglobulins found in SS are cryoglobulins which, symptoms, such as fever, weight loss or night sweats, in the majority
in turn, have been found in about 10- 20% of patients (~75%) of patients [90].
[62,66,69,79,81,83,87]. The most frequent type of cryoglobulinemia in There are various clinical and laboratory factors that may help
SS is a mixed monoclonal IgM with polyclonal IgG [81,87]. Monoclonal predict the development of NHL in SS. The most consistent NHL pre-
immunoglobulins in SS have been associated with pulmonary mani- dictors in the literature include parotid enlargement, lymphadeno-
festations (25% vs 8%, P = 0.034) and hematologic malignancies (12% pathy, palpable purpura, low C4 complement level, and the presence of
vs 1.6%, p = 0.004; OR 8.13, 95% CI 1.6 - 51.5) [80]. Cryoglobuli- cryoglobulinemia [98]. Other, less consistent NHL disease predictors
nemia in particular is an important marker of systemic involvement and include splenomegaly, low C4 complement level, lymphopenia, neu-
poor prognosis in SS. Its presence has been associated w/ cutaneous tropenia, and a monoclonal component in the serum or urine [90,98].
vasculitis (56% vs 8%, p < 0.001) [87], hypocomplementemia (75% vs More recently reported predictors include elevated rheumatoid factor
2%, p < 0.001) [87], and glomerulonephritis [69,81,88]. More im- level [93,99], a focus score of greater than 3 or the presence of ectopic
portantly, cryoglobulinemia is a risk factor for developing lymphomas. germinal center-like lesions on minor salivary gland biopsy [98,99],
This was demonstrated in a prospective Greek study completed over a and increased overall systemic activity with an ESSDAI score of greater
5-year period of 103 pSS subjects who at baseline were tested for than or equal to 5 [93]. The presence of multiple risk factors is felt to
cryoglobulinemia and had no known lymphoma [81]. Over the 5-year confer a greater risk of developing NHL [98].
period, 7 subjects (6.8%) developed B-cell lymphomas. Six of the 7 Although lymphoma most frequently presents as persistently
(86%) who developed lymphoma had baseline cryoglobulinemia com- swollen parotid glands, it is important to note that parotid enlargement
pared with 12 of 96 (12.4%) who did not develop lymphoma, thus is common in SS and may be due to autoimmune inflammatory siala-
indicating that the presence of cryoglobulinemia was a moderate risk denitis, infection, obstruction, or other causes. When due to NHL, it is
factor for lymphoma development (r = 0.421, p = 0.0009). more typically unilateral, persistent, and sometimes indurated and

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nodular [90]. In addition to careful history taking and examination, Two small studies prospectively evaluated autonomic dysfunction in
imaging with an MRI scan and/or ultrasound may be helpful in the at risk SS cohorts and reported a prevalence of gastroparesis ranging
evaluation [90]. Biopsy confirmation is necessary whenever the diag- from 29-53% [121,122]. One study suggests that dysmotility in SS
nosis is in doubt or lymphoma is suspected. Lymphadenopathy is also could be due to autoantibodies that may inhibit muscarinic receptor-
fairly common in SS and noted in 8-32% [62,68,83]. Splenomegaly is mediated cholinergic neurotransmission [123]. This diagnosis should
less common and was observed in 7% according to one series [62]. therefore be considered in any SS patient with chronic nausea, vo-
The prognosis of NHL in SS is typically good, especially with the miting, anorexia, early satiety or weight loss in whom a prior upper
MALT subtype. For example, one retrospective study of 53 cases noted a endoscopy is normal.
3-year survival of 97% and event-free survival of 78% [90]. When
higher grade lymphomas occur, however, mortality rates can be sig- 2.3.15. Intestinal
nificantly higher [100,101]. Chronic diarrhea in Sjögren’s syndrome has been described in up to
9% of patients [124] and represents a complex diagnostic challenge.
2.3.12. Gastrointestinal manifestations Biopsy-proven celiac disease may occur in SS but prevalence seems to
There are variety of gastrointestinal (GI) manifestations that have vary in different populations. Two studies reported the presence of
been described in SS. These may occur due to lymphocytic infiltration biopsy-proven celiac in 4.5-15% of patients with SS [125,126] com-
of the GI mucosa or exocrine glands, autonomic neuropathies or the pared with the general population (0.5%); however, other studies have
development of associated autoimmune diseases that occur with in- shown contrasting results with 0.9% of 114 patients in one study and
creased frequency in SS. Rarely vasculitis of the gastrointestinal tract 0% of 400 patients in another [63,127]. Hypersensitivity to certain
may also occur. foods in the absence of proven celiac disease may also aggravate
symptoms such as bloating and diarrhea. One study reported im-
2.3.13. Esophageal provement of gastrointestinal symptoms and arthralgias with dietary
Dysphagia, often described as the feeling of food getting "stuck" in restriction of foods to which hypersensitivity was demonstrated. This
the throat or chest, is a common complaint among SS patients. One case was followed by a recurrence of symptoms upon re-challenge with the
control study noted dysphagia in 65% of those with pSS compared with offending foods [128]. Systemic secretagogues (e.g. cevimeline, pilo-
3% of controls (p < 0.01); esophageal symptoms were noted in 80% carpine) that are used to treat xerostomia and other sicca symptoms
and pharyngeal symptoms in 45% of SS subjects [102–104]. Numerous may cause diarrhea and other GI symptoms related to cholinergic side
causes have been identified including esophageal dysmotility, esopha- effects especially when used at higher doses. Likewise, the excessive use
geal webs, Zenker’s diverticula, achalasia, reflux and lack of saliva flow of lozenges for dry mouth that contain xylitol or sorbitol as the artificial
[105–108]. When empiric treatment fails, evaluation with an upper sweetener can also cause flatulence, bloating and diarrhea. Other rare
endoscopy, barium swallow with video esophagram and, occasionally, causes of diarrhea in SS patients may include concomitant in-
esophageal manometry may be necessary. flammatory bowel disease [129,130], small intestinal bacterial over-
Gastroesophageal reflux (GER) also commonly occurs in SS and may growth syndrome (SIBO) [131,132] or lymphocytic colitis [133].
cause or contribute to various symptoms including: heartburn, hoar- Vasculitis involving the GI tract in SS is uncommon and only
seness, chronic cough, nausea, chest pain and dysphagia. The same case documented in about 13 case reports to date [102,134]. It is frequently
control study mentioned above noted a GER prevalence of 60% in pSS associated with cryoglobulinemia [102]. Although quite rare, this di-
patients compared to 23% in controls (p < 0.01) [103]. A cross-sec- agnosis should be considered in any SS patient with severe abdominal
tional population-based study in Taiwan found the risk of GER to by 2.4 pain, GI bleeding, infarcted bowel or perforation.
times greater in 4650 SS patients than controls after adjusting for age, Constipation occurs in SS more frequently than diarrhea and may
sex and comorbidities [109]. Potential contributors to GER in SS may result from lack of saliva flow or dysmotility. One small Scandinavian
include diminished saliva, decreased esophageal motility, sphincter study noted that bowel symptoms were found more frequently in SS
relaxation, delayed gastric emptying time, or side effects of medications patients than controls including constipation (23% vs 3%), incomplete
[109]. One study noted a delay in clearance of acid from the esophagus rectal emptying (27% vs 7%), and abdominal pain (27% vs 3%, all
in SS patients with GER and suggested dysmotility as a cause [110]. p < 0.05) [135].
Additionally, in SS the acid neutralizing capacity of saliva is diminished There has been a lot of interest lately in the role that intestinal
due to altered pH and decreased volume. Secretion of epidermal growth microbial composition plays in health and disease. Abnormal intestinal
factor by the submandibular glands which inhibits gastric acid pro- microbiota, also called dysbiosis, has been associated with autoimmune
duction may also be decreased [111,112]. diseases including SS [136]. One small study demonstrated that severe
dysbiosis was more prevalent in SS patients than controls (21% vs 3%, p
2.3.14. Gastric = 0.018) and was associated with higher disease activity (ESSDAI 13 vs
Common gastric complaints among SS sufferers include nausea, 5, p = 0.049) [136].
dyspepsia and epigastric pain [113]. The incidence of chronic atrophic
gastritis is higher in SS than normal controls [114] and may be asso- 2.3.16. Pancreatic
ciated with altered mucosal function, hypochlorhydria, achlorhydria, Most pancreatic involvement in SS relates to pancreatic exocrine
hypopepsinogenemia and hypergastrinemia [113,115–117]. Biopsy insufficiency and is typically asymptomatic; altered pancreatic function
studies typically show mononuclear cell infiltration of the mucosa and has been found in 36-63% of patients and varies depending on the
glandular atrophy with varying degrees of intestinal metaplasia method of evaluation [102,137–140]. Acute pancreatitis is mentioned
[113,118]. Although Helicobacter pylori infection and anti-gastric par- in some series but is rare. The clinical diagnosis of chronic pancreatitis
ietal cell antibodies occasionally occur in SS the significance of these is also uncommon in SS [102]. One large series noted that chronic
findings remains unclear [102]. In one study the eradication of H. pylori pancreatitis was present in less than 2% of pSS patients [102,141–143]
infection failed to improve dyspepsia and/or tissue atrophy in those whereas another found it in ~5% [144]. Several unusual cases dating
with SS [119]. H. pylori infection, like SS, is a known risk factor for back to the 1970's describe a triad of sclerosis cholangitis, chronic
MALT lymphoma, although, at the present time, there is little evidence pancreatitis and SS [142,145]. The majority of these cases were male,
to suggest that having both H. pylori and SS confers an additive lym- and many had salivary gland swelling in addition to sicca symptoms.
phoma risk [120]. Since chronic pancreatitis is a prototypical manifestation of IgG4 re-
Dysautonomia has been described in SS and may affect the gastro- lated disease [146], this diagnosis must always be excluded before
intestinal tract. chronic pancreatitis and other symptoms can be attributed to SS.

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2.3.17. Hepatic often be established on clinical grounds though liver biopsy may be
Liver enzyme abnormalities have been found in ~10-40% of SS necessary [155]. Among patients with AIH, SS has been reported in up
patients and may be caused by drug toxicity, primary biliary cirrhosis, to 7% [155]. AIH is a rare manifestation of SS, having been reported in
chronic active autoimmune hepatitis (AIH) and sclerosing cholangitis about 1% of pSS in a large registry of 866 pSS patients and in up to 4%
(SC) [102,147–150]. Although considered an exclusionary diagnosis in in other studies [68,102]. All of these have been type I AIH. Type II AIH
the last 3 classification criteria sets for SS, chronic hepatitis C infection has not been reported in patients with pSS [161]. About 10% of AIH
(HCV) should always be tested in any patient with sicca symptoms and patients also have a positive AMA and are felt to have an AIH/PBC
abnormal liver function tests. Hepatitis C is highly prevalent among overlap syndrome [161]. In one study looking at patients with an AIH/
"baby boomers" in the United States [151] and certain European po- PBC overlap, SS was reported in 8%, more than any other systemic
pulations [152] and, can cause a clinical syndrome that closely re- autoimmune disease [161]. Although AIH can progress to cirrhosis and
sembles SS [153] Diagnosis of the HCV-associated sicca syndrome re- even hepatocellular carcinoma (HCC), when properly treated, few de-
quires demonstration of viral persistence in blood or saliva by velop cirrhosis at follow-up and the 10-year survival rate is greater than
polymerase chain reaction or documentation of chronic liver disease 90% [155]. Treatment typically consists of prednisone with or without
consistent with HCV in a patient with negative anti-SSA/SSB. azathioprine [155].
Primary biliary cholangitis (PBC) is an autoimmune disease of the Sclerosing cholangitis (SC) is a liver disease characterized by pro-
bile ducts leading to bile duct destruction, cholestasis, and liver failure gressive inflammation and fibrosis of the intra- and extra-hepatic bile
[154]. There is a female to male ratio of 9:1 with a prevalence that ducts leading to significant morbidity and mortality [155,161]. It is rare
various by geography and an onset typically between 40 and 60 years of with a prevalence of 10 per 100,000 in the United States and may
age [155]. Patients with PBC often present with fatigue and pruritus yet present with abdominal pain, nausea, and jaundice [155,161]. Though
~50-60% are asymptomatic at diagnosis [156]. It is interesting to note it can be found in 7% of IBD patients, SC is scarcely found in SS with
that subjective and objective evidence of dry eyes and dry mouth are only 13 cases noted in the literature [155,161]. Interestingly, 12 of the
frequently noted (~30-70%) in PBC patients [102,157]. PBC has been 13 SS/SC cases also had chronic pancreatitis. Despite treatment with
reported in ~2% of pSS patients in a large registry of 866 pSS patients medications and endoscopic interventions, the median time to liver-
[68] and in ~4-5% in smaller studies [62,150,158]. Among those with transplant or death in SC patients is 18 years [155].
PBC, SS is common. The prevalence of SS has been reported as 36% in
one study of 322 PBC patients and as 10% in another of 1032 PBC 2.3.18. Renal manifestations
patients [102,159,160]. Diagnosis of PBC is can be made with elevated Clinically overt renal disease is unusual in SS, reported in about 5%
levels of alkaline phosphatase (> 2x the upper limit of normal) or GGT of patients in large retrospective studies [66,83,88]. However, the most
(> 5x the upper limit of normal), anti-mitochondrial antibody (AMA) common renal manifestations, tubulointerstitial nephritis and renal
testing, and/or chronic granulomatous cholangitis on liver biopsy tubular acidosis, are often subtle and insidious, frequently presenting
[155]. AMA (with an M2 pattern) testing is highly sensitive (95%) and asymptomatically and with seemingly insignificant laboratory ab-
highly specific (98%) for the diagnosis [154,155] and is usually positive normalities [164,165]. When specifically looking for these manifesta-
years before the diagnosis of PBC is made [155]. Positive AMA testing tions in prospective studies, the prevalence of renal disease in SS has
has been reported in ~2-8% of SS patients, 1/2 of whom had no clinical been shown to be as high as 50% [166]. More dramatic renal pre-
or laboratory evidence of liver disease [102,161]. With the high sen- sentations such as acute glomerulonephritis is noted in a minority of
sitivity and specificity of the AMA test, it is not surprising that in studies cases. The onset of clinically significant renal disease in SS seems to
of non-SS patients with no overt evidence of liver disease, those with occur around the time of SS diagnosis or shortly thereafter though
positive AMAs still had a high risk of going on to develop symptomatic ~10% may occur 5 or more years later [167]. Overall, among those
PBC [161]. Given the fact that AMA testing is highly accurate for a with renal involvement, the loss of renal function tends to be mild with
disease that is frequently asymptomatic at presentation and can pro- only ~5-10% progressing to end-stage kidney disease [167]. Active
gress to liver failure, some authors have recommended routine AMA vigilance for renal manifestations of SS is crucial as early diagnosis can
testing in SS patients, even in the absence of evidence of overt liver potentially help prevent renal failure and other sequelae.
disease [102,162]. These authors note that early use of ursodeoxycholic
acid (UDCA) in such patients could potentially prevent progression to 2.3.19. Tubulointerstitial nephritis
cirrhosis [162,163]. The prognosis of PBC is generally good with only a Though many may equate glomerulonephritis with autoimmune
minority of those treated with UDCA evolving to cirrhosis and 2 out of 3 disease, the most common renal lesion found in those with SS is tu-
PBC patients treated with UDCA have a nearly normal life expectancy bulointerstitial nephritis (TIN). One large retrospective French study of
[155]. 95 SS patients with biopsy-proven renal involvement found TIN in 98%
Autoimmune hepatitis (AIH) is a chronic disease characterized by of the biopsies, ~75% of which occurred in isolation without glomer-
autoimmune destruction of hepatocytes, increased serum auto- ulonephritis ("isolated" TIN) [167]. Smaller studies looking specifically
antibodies, increased serum aminotransferases, increased gamma-glo- at renal biopsies note TIN in ~50-80% of biopsy samples
bulin levels, as well as typical but non-specific findings on liver biopsy [88,164,166,168].
[155]. There is a female to male ratio of 4:1 and an incidence estimated TIN in SS typically presents and progresses insidiously with minimal
at 1 per 100,000 person-years [155]. The onset usually occurs prior to symptoms if any at all [165]. This is why, without specifically screening
45 years of age and is typically insidious [155]. Signs and symptoms for it, it is under-diagnosed and reported as infrequent in large retro-
may include fatigue, anorexia, jaundice, hepatosplenomegaly, rash, and spective cohorts [165,167]. Clues for TIN in SS may include electrolyte
arthralgia [155]. There are two types of AIH, type I and type II [155]. disturbances, elevations in serum creatinine, and low range proteinuria
Type I is associated with ANA and/or anti-smooth-muscle antibodies [165]. The rise in creatinine is often subtle and acute kidney injury is
(anti-SM) (found in up to 80% of cases) [155]. Type II is associated with uncommon [165]. The low molecular weight proteinuria (tubular
anti-liver kidney microsomal type I antibodies (anti-LKM) [155]. Other proteinuria) found in TIN can be missed since it is not detected on urine
autoantibodies that can be associated with AIH include anti-LC1 (cor- dipstick testing [165]. Hypertension tends to occur late in the disease
relates w/ more severe disease), p-ANCA, anti-SLA/LP (10-30%), anti- course [165].
asialoglycoprotein receptor antibodies (correlates w/ more severe dis- The pathophysiology of TIN consists of inflammation of the inter-
ease) [155]. Less specific autoantibodies found in AIH include anti- stitium which causes tissue fibrosis and atrophy that ultimately leads to
cardiolipin (40%), anti-chromatin, anti-dsDNA (up to 34%), RF, anti- chronic kidney disease and, in many cases, renal tubular acidosis
histones (up to 35%), SSA, and CCP (9%). The diagnosis of AIH can [165,169]. Auto-antibodies, such as those against the carbonic

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anhydrase of the intercalated cells, have been found but it is not clear if bicarbonate, metabolic acidosis can result in a process known as
these are a cause or an effect of TIN [165]. The inflammatory infiltrate proximal renal tubular acidosis (pRTA). pRTA is rare, having been re-
of TIN is made mostly of T-cells, B-cells and plasma cells [165,167]. The ported in 3% of SS patients with renal involvement [174]. In addition to
T-cells predominate and are mostly CD4+ [167,170]. This overall bicarbonate, there may also be a failure to reabsorb phosphate, small
pattern is similar to that found in minor salivary gland infiltration in SS proteins, amino acids, glucose and urate (a condition known as Fanconi
[165,167]. The pattern and degree of infiltration in TIN is highly syndrome [170]. As with dRTA, pRTA in SS is often asymptomatic
variable. It can be diffuse or patchy [165,169]. It can be light, invol- though it may result in osteomalacia, nephrolithiasis and ne-
ving < 25% of the interstitium, to heavy, involving > 75% of the in- phrocalcinosis [165,170].
terstitium [167,169]. Permanent damage, in the form of fibrosis and
atrophy, is often found [165]. The Jasiek, et al. study noted that over 2.3.22. Diabetes insipidus
25% of the cortex was fibrosed in about 2/3 of the biopsies and that this Nephrogenic diabetes insipidus is a condition in which the principal
is a strong marker for poor renal prognosis [167]. It is important to note cells of the collecting duct are unable to properly concentrate urine
that the histology of TIN in SS is nonspecific and therefore it is im- leading to polyuria, nocturia, and polydipsia [170]. This is a fairly
portant to consider the differential diagnosis for TIN when encountered frequent finding occurring in 17-28% of SS patients according to pro-
[165]. The differential diagnosis for TIN includes IgG4 related disease spective studies [164,170,172]. The management of diabetes insipidus
(look for increased staining for IgG4+ plasma cells & storiform fi- is simply to drink enough water which is commonly done by SS patients
brosis), sarcoidosis (look for granulomas), infections such as pyelone- anyway for symptoms of dry mouth and throat.
phritis, tuberculosis, leptospirosis, hantavirus infection, and the use of
drugs such as NSAIDs, beta-lactam antibiotics, allopurinol, the tubu- 2.3.23. Glomerulonephritis
lointerstitial nephritis and uveitis syndrome (TINU), lymphoma, leu- Unlike TIN which typically presents insidiously, glomerulonephritis
kemia, and the use of Chinese herbs [165]. (GN) in SS often presents in a dramatic fashion with hypertension,
Case series of TIN in SS note a good response to glucocorticoids at proteinuria, hematuria, and acute kidney injury [165]. The most
doses > 0.5 mg/kg/d [165,166]. Though some series report improve- common GN lesion found in SS is membranoproliferative glomer-
ment with concurrent immunosuppressive medication such as myco- ulonephritis which is typically due to immune complex deposition as-
phenolate mofetil, there is no clear evidence that this strategy is su- sociated with cryoglobulinemia and low complement levels
perior to glucocorticoids alone [165]. In regards to the prognosis of TIN [88,165,167,170]. GN is not common in SS. According to two pro-
in SS, it seems there is a slow decline in renal function sometimes spective SS cohorts, the prevalence of GN was found to be only ~2%
leading to end-stage kidney disease. One retrospective study reported [62,172]. Of renal biopsy samples, Jasiek et al. noted glomerular le-
that ~15% of SS patients with TIN required hemodialysis [88]. sions in 23.2%, mostly with concurrent TIN [167]. Studies with far
fewer samples have shown a GN frequency of 8% to 48% [88,164,168].
2.3.20. Distal renal tubular acidosis GN presents later in the disease course than TIN [88] [69,152].
Renal tubular acidosis is a condition in which the kidneys are un- Treatment is typically with high-dose glucocorticoids and other im-
able to fulfill their function of maintaining proper acid-base balance in munosuppressive medications like mycophenolate mofetil, rituximab,
the body due to abnormalities of cells of the renal tubules resulting in and cyclophosphamide [165]. GN in SS has been associated with NHL
metabolic acidosis. The most common cells involved in this process in and decreased mortality [88,165,170].
SS are the alpha-intercalated cells of the collecting duct. The job of
these cells is to secrete hydrogen ions into the urine to help keep the 2.3.24. Pulmonary manifestations
blood from becoming too acidic. In distal renal tubular acidosis (dRTA), Clinically significant pulmonary involvement occurs in 10-20% of
due to a loss of the hydrogen ATPase enzyme, these cells fail to secrete SS patients and is a significant cause of disease-related mortality
adequate amounts of hydrogen ions in the urine and this results in a [62,66,69,83,175–178]. The most common pulmonary manifestations
non-anion-gap metabolic acidosis [165]. To maintain electroneutrality, are airway disease, interstitial lung disease (ILD), and xerotrachea
other cations are secreted instead such as potassium, calcium, and [175,176,178,179]. The most common respiratory symptoms in SS are
phosphorous. The loss of potassium can lead to severe hypokalemia that cough and dyspnea though some with abnormal objective pulmonary
may interfere with muscle function and manifest as cramps and/or findings are asymptomatic [177,178] [159,160].
periodic paralysis [165]. The loss of calcium and phosphorous can lead
to nephrolithiasis and/or nephrocalcinosis [170]. The mild metabolic 2.3.25. Respiratory infections
acidosis can lead to bone loss and/or osteomalacia [166,171]. More Recurrent respiratory tract infections such as sinusitis and bron-
recent prospective and cross-sectional studies specifically looking for chitis are not uncommon in SS with pneumonia reported in 10-35%
renal abnormalities in SS patients show that dRTA occurs in ~10-40% [176]. Potential contributors to recurrent respiratory tract infections
of SS patients [166,171–173] and a retrospective study notes that dRTA may include decreased mucociliary clearance, gastroesophageal reflux,
was found in ~70% of SS patients with renal involvement [170,174]. bronchiectasis and immunosuppression [176].
Distal renal tubular acidosis can be the first and only renal abnormality
in patients with SS and may present in a subtle fashion [165]. Mild 2.3.26. Cough
hypokalemia, hyperchloremia, non-anion-gap metabolic acidosis, or a Chronic cough is reported in up to 60% of SS patients and may affect
history of nephrolithiasis in a SS patient should tip one off to the pos- quality of life [176]. One study noted that cough in SS was productive
sibility of an underlying dRTA [165]. Occasionally a so-called "in- in about half of cases and dry in the other half [175]. Potential causes of
complete" version of dRTA may exist in which there is no acidemia but cough in SS include xerotrachea, airway hyperresponsiveness, bronch-
the urine pH fails to decrease to < 5.3 after an ammonium chloride acid iectasis, gastroesophageal reflux, and ILD [176].
load [165]. dRTA in SS is usually associated with TIN [165]. Because of
this, if dRTA is discovered in a SS patient, a renal biopsy should be 2.3.27. Pulmonary testing
strongly considered [165]. The treatment of dRTA is typically suppor- Given the morbidity associated with the pulmonary manifestations
tive including bicarbonate and potassium supplements along with close of SS routine screening is recommended for every patient with chronic
monitoring by a nephrologist [170]. respiratory symptoms. Evaluation for lung disease in SS may include
pulmonary function testing (PFT), high-resolution computed tomo-
2.3.21. Proximal renal tubular acidosis graphy (HRCT) scanning, and lung biopsy. The diagnostic yield of these
When cells of the proximal tubule fail to properly reabsorb studies was described in a systematic literature review that noted

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pulmonary involvement in 795 (16%) of 4897 SS patients diagnosed by [176]. Lung biopsy should always be performed in patients with
AECG criteria [178]. consolidating nodules, mass-like opacities, mediastinal adenopathy or
Among 330 patients tested PFT results were abnormal in 64%. A treatment refractory cases to rule out lymphoma [176].
restrictive pattern was noted in ~65% and an obstructive pattern in
~20%. 2.3.28.4. OP. The HRCT pattern typical of OP consists of multiple
HRCT findings were described in 526 patients. The most common areas of consolidation in the periphery sometimes with ground glass
CT findings were bronchiectasis/bronchiolitis (50%) and ground-glass opacities and centrilobular nodules [176]. In doubtful cases a biopsy is
opacities (50%). Less frequent findings included: pulmonary nodules required to confirm this diagnosis. The pathology will show polypoid
(23%), interlobular septal thickening (23%), reticular opacities (22%), intraluminal masses of fibroblasts, myofibroblasts and collagen within
cysts/bullae (22%), airspace opacities (14%), honeycombing (13%), the alveolar ducts and spaces surrounded by alveoli and bronchioles
non-septal linear/plate-like opacities (12%), mosaic perfusion/at- with coexistent chronic inflammation.
tenuation (7%), tree-in-bud opacities (6%), emphysema/air trapping
(5%), and pleural thickening/effusions (5%). 2.3.29. Airway disease
Of the 146 SS patients who underwent lung biopsy the most Manifested mainly by cough, airway involvement in SS is due to
common histopathologic findings included: non-specific interstitial dryness from exocrine gland dysfunction and/or lymphocytic infiltra-
pneumonia (NSIP) in 45% followed by bronchiolitis in 25%, usual in- tion of the trachea, bronchi, and/or bronchioles [176]. Bronchial hy-
terstitial pneumonia (UIP) in 16%, lymphocytic interstitial pneumonia perresponsiveness to environmental stimuli is noted in up to 60% of SS
(LIP) in 15%, and organizing pneumonia (OP) in 7%. Less common patients [176]. CT findings related to airway disease include bronch-
findings included amyloidosis (6%), pulmonary lymphoma (4%), and iectasis, bronchiolectasis, airway wall thickening, centrilobular no-
non-caseating granulomas (3%). dules, tree-in-bud opacities, mosaic attenuation, air trapping, and
subsegmental atelectasis [175,176]. Airway disease typically has
2.3.28. Interstitial lung disease minimal effect on respiratory function and, therefore, is not a sig-
Interstitial lung disease (ILD) has been reported in 3-11% of SS nificant contributor to mortality in SS patients [176].
patients and is a significant cause of mortality [176,177]. Most patients
present with dyspnea and cough. A restrictive pattern is typically noted 2.3.30. Uncommon pulmonary manifestations
on PFTs with a diminished diffusing capacity of carbon monoxide Pleurisy and pleural effusions may occur in SS albeit rarely
[176]. One recent French series of 264 consecutive SS patients with a [180–183]. The effusion can be unilateral or bilateral and is usually
mean follow-up of 24 months noted ILD in 8% (21/263) [177]. Similar exudative with a lymphocytic predominance.
to the findings mentioned in the large systematic review noted above, Pulmonary hypertension documented by cardiac catherization has
the most common ILD patterns were NSIP in ~30%, followed by UIP in also been described in SS and causes morbidity and mortality similar to
~25%, LIP in ~10%, OP in ~10%, and non-specific findings in the rest. that seen in other connective tissue disorders [184,185].
The onset of ILD preceded SS diagnosis in ~25%, was concurrent in
~25%, and followed the diagnosis in ~50%. Clinical presentations 2.3.31. Dermatologic manifestations
were varied and acute/subacute in ~50%, insidious in ~25%, and Sjögren's syndrome commonly affects the skin and dermatologic
asymptomatic or subclinical in ~25%. The disease courses of the 21 manifestations of SS often precede sicca symptoms of dry eye and dry
patients after follow-up demonstrated improvement in ~15%, stabili- mouth [186]. The most frequent is xerosis (dry skin), occurring in about
zation in ~50%, and deterioration in ~35%. Factors at the time of SS 50%. Other relatively common skin manifestations include Raynaud’s
diagnosis that predicted the development of ILD included older age (63 phenomenon (~15-30%), cutaneous vasculitis (~10%), and annular
vs 55 years, p = 0.044), Raynaud’s phenomenon (57.1% vs 22.2%, p = erythema (~10%) [62,66,68,69,186].
0.001), and esophageal involvement (23.8% vs 2.7%, p = 0.001). Raynaud’s phenomenon (RP) is a clinical diagnosis that typically
Factors associated with a deteriorating course included older age (p = manifests as sudden-onset well-demarcated color changes of the distal
0.038) and esophageal involvement (p = 0.038). digits that last up to 30 minutes or so and then resolve. The classic
pattern of color change is white to purple/blue then red though this
2.3.28.1. NSIP. NSIP is the most common subtype of ILD in SS [176]. pattern is noted in a minority of patients. Though RP can lead to distal
The histopathology consists of interstitial inflammation and fibrosis digital ulceration from repeated episodes of ischemia, this is rarely
with a uniform appearance and relative preservation of the lung noted in SS and more typically found in systemic sclerosis. As such,
architecture [176]. The HRCT pattern is typically bibasilar and discovery of digital ulcers in a SS patient with RP should prompt an
symmetric with reticular changes, traction bronchiectasis, and ground evaluation for concurrent systemic sclerosis [186].
glass opacities. [176]. The response to treatment is variable but most Cutaneous vasculitis in SS can manifest as purpura, maculopapular
patients demonstrate improvement or stabilization of their lung disease rash, urticaria, and cutaneous ulcers [186]. The location of these
with a 5-year survival rate of 83% [176]. findings is typically on the lower extremities [186]. Pathologically, the
most common finding is leukocytoclastic vasculitis followed by cryo-
2.3.28.2. UIP. UIP is the next most common subtype of ILD in SS and globulinemic and urticarial vasculitides [186]. Overall, cutaneous
the HRCT pattern is characterized by reticular changes, bronchiectasis, vasculitis in SS is associated with more systemic manifestations, more
and honeycombing that is patchy and predominates at the bases and severe disease, lymphoma and poor prognosis [186]. In one study of
periphery [176]. Histopathology reveals honeycombing, minimal 515 SS patients followed for a mean of 110 months, those with cryo-
interstitial inflammation and patches of interstitial fibrosis intermixed globulinemic vasculitis had a higher risk of death compared to those
with normal parenchyma [176]. UIP is difficult to treat and has a worse without cryoglobulins (HR 4.36, 95% CI: 1.32, 14.47) [187].
prognosis than NSIP [176]. Annular erythema (AE) in SS resembles subcutaneous lupus er-
ythematosus (SCLE) and, as suggested by its name, appears as poly-
2.3.28.3. LIP. Histopathology of LIP consists of diffuse polyclonal cyclic erythema. AE in SS and SCLE can be difficult to tell apart as they
lymphocytic interstitial infiltrate with lymphoid follicles and germinal essentially appear the same morphologically and are both associated
centers [176]. Follicular bronchiolitis is often associated with LIP. The with SSA positivity [186]. AE in SS is associated less severe systemic
HRCT pattern typical of LIP consists of nodules, ground-glass opacities, disease and better overall prognosis [186].
thickening of the interlobular septa, and cysts in ~60-80% [176]. Most Amyloidosis is rarely found in SS but when it is, it is typically lo-
SS patients with LIP stabilize or improve with glucocorticoid therapy calized to the skin and/or lungs [186]. Localized cutaneous amyloidosis

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(LCNA) appears as a single nodule, sometimes multiple nodules, mostly Mononeuritis multiplex is a painful condition in which damage to
on the legs, arms, trunk and face [186]. Although LCNA is rare, 25% of two or more nerves occurs in succession in an acute/subacute fashion
reported cases have been associated with SS [186]. leading to sensory and motor deficits [195,196]. It can present as foot
Less common dermatologic manifestations noted in SS include drop or wrist drop with patchy sensory loss or as an asymmetric per-
pruritis, vitiligo, alopecia, anetoderma, Sweet syndrome, lichen planus, ipheral neuropathy. Symptoms usually begin in lower limbs and affect
granulomatous panniculitis, sub corneal pustular dermatosis, erythema the tibial or peroneal divisions of the sciatic nerve. Inflammation of
elevatum diutinum, erythema multiforme-like, erythema perstans-like, epineural and perineural blood vessels that perfuse the involved nerves
and erythema nodosum-like lesions [186]. leads to infarction. Electrodiagnostic studies demonstrate an asym-
metric peripheral neuropathy involving 2 or more sensory or motor
2.3.32. Neurologic manifestations nerves. A sural nerve or superficial peroneal nerve biopsy or simulta-
The prevalence of neurologic disease in SS is ~20% and the per- neous nerve-muscle biopsy will show definite vasculitis in up to 77% of
ipheral nervous system (PNS) is more frequently affected than the cases [197]. This vasculitis often affects other organs at the same time
central nervous system (CNS). Neurological symptoms, however, in- and causes constitutional symptoms. Mononeuritis multiplex in SS has a
cluding headaches, cognitive dysfunction and affective disorders have strong association with serum cryoglobulinemia [188]. The prevalence
been observed in as many as ~70% [188–190]. The onset of neurologic of mononeuritis multiplex in SS is noted to be 12% in some studies
disease in SS frequently predates the diagnosis of SS and often occurs in [189]. Mononeuritis multiplex is a very serious manifestation that re-
the absence of sicca symptoms [188,191]. Not surprisingly, this may quires expeditious evaluation and treatment with immunosuppressive
delay treatment until the diagnosis of SS is established. Typically, therapy.
neurologic manifestations in SS patients are mild and treatment is
supportive. However, occasionally, cases are progressive and/or de- 2.3.34. Cranial neuropathy
bilitating and warrant consideration of immunomodulating/im- In two large cohorts of SS patients with neurological disease the
munosuppressive therapy. prevalence of peripheral cranial neuropathies ranged from 16-20%
[191,192]. Pure sensory trigeminal neuralgia is frequently described in
2.3.33. Peripheral nervous system involvement most series and typically affects the maxillary branch of the trigeminal
Peripheral nervous system (PNS) manifestations in SS include ax- nerve in a unilateral distribution [189]. The major symptom is lanci-
onal sensory/sensorimotor polyneuropathies, small fiber sensory neu- nating or searing facial pain that last seconds to minutes and can occur
ropathy, sensory ataxic neuronopathy (also known as sensory gang- spontaneously or be triggered by touching the face, chewing, speaking
lionopathy), cranial nerve neuropathies, radiculoneuropathy, or brushing the teeth. Other common symptoms related to cranial
autonomic neuropathies, chronic inflammatory demyelinating poly- neuropathies include hearing loss and vestibular symptoms (cochlear
neuropathy and mononeuritis multiplex [188,189]. The most common nerve), recurrent diplopia (CN III, VI) and Bell's palsy (CN VII). Multiple
patterns are axonal sensory polyneuropathies and small fiber sensory cranial neuropathies in the same patient have also been described
neuropathies [188,189]. More than one neuropathy type may coexist in [192].
any given patient [192].
Distal axonal sensory polyneuropathy affects large nerve fibers and 2.3.35. Central nervous system involvement
is the most common PNS manifestation of SS [189]. It typically presents Central nervous system (CNS) involvement in SS varies greatly in
with indolent, mild paresthesias of the distal lower extremities and, the significance ranging from mild cognitive dysfunction to transverse
upper extremities are involved in about 20% of cases [189]. On exam, myelitis and resultant paralysis [188,189]. Other manifestations in-
there are sensory deficits to light touch, proprioception and vibration of clude aseptic meningitis, seizures, headaches, optic neuritis, dis-
the affected extremity in a "stocking-glove" distribution and diminished seminated encephalopathy, and multiple-sclerosis-like demyelinating
or absent deep tendon reflexes. Electrodiagnostic studies are frequently lesions [189–191,198,199].
abnormal. Sensorimotor polyneuropathy occurs when there is con- Demyelinating CNS lesions can occur in the white matter of the
current weakness. The weakness is generally mild and affects the toe/ brain and spinal cord of patients with SS and mimic the relapsing-re-
foot extensors [188,189]. mitting and primary progressive forms of multiple sclerosis (MS). This
Small fiber neuropathy occurs when there is damage to the A-δ can cause various symptoms including visual loss (optic neuritis), par-
small myelinated fibers and/or unmyelinated C fibers that conduct esis of limbs, ataxia, sphincter dysfunction, cognitive dysfunction and
signals of pain and temperature and leads to burning paresthesias and sensory symptoms [189]. Features that help distinguish SS from MS
shooting pain often with allodynia and hyperalgesia [193]. It is esti- may include a lack of oligoclonal bands (OCB) on cerebral spinal fluid
mated to affect 5-10% of SS patients [189]. Symptoms can be sym- analysis (OCB is noted in 95% of MS and only 30% of SS), the presence
metric and affect mainly the distal extremities or they can be patchy of longitudinally extensive transverse myelitis on MRI (common in SS-
[188]. The onset of symptoms is typically subacute or chronic [189]. related transverse myelitis and highly atypical in MS), and the white
On exam, there is a loss of pinprick and temperature sensation but no matter lesions demonstrated on brain MRI in SS that, unlike in MS, do
deficit in strength, light touch sensation, proprioception, or deep not enhance and tend to spare the corpus callosum [188]. The presence
tendon reflexes [188]. Nerve conduction studies are characteristically of extra glandular manifestations such as arthritis and interstitial lung
normal; diagnosis is made by skin biopsy demonstrating a decrease in disease also help confirm a suspected diagnosis of SS.
intraepidermal nerve fiber density [193]. It must be kept in mind, however, that non-specific white matter
Sensory ataxic neuronopathy, also known as ganglionopathy, is a lesions are not infrequently found on brain MRI of SS patients and
rare and often dramatic type of neuropathy found in SS [194]. Damage sometimes related to other causes. Without corresponding neurologic
to the dorsal root ganglia from lymphocytic infiltration (ganglionitis) signs or symptoms, these are often not clinically significant and prob-
leads to a marked loss of proprioception, sensory ataxia and difficulty ably reflect microvascular ischemic changes related to cardiovascular
with fine motor skills [189]. Patients often present with gait instability risk factors and not autoimmunity [188].
that eventually requires the use of a wheelchair to prevent falls. Deep Like other autoimmune disorders SS has also been associated with
tendon reflexes are diminished or absent and vibration sensation is neuromyelitis optica (NMO) or Devic syndrome [51,200,201]. NMO is
abnormal with preservation of motor function. Nerve conduction stu- an autoimmune disease characterized by optic neuritis, longitudinally
dies demonstrate decreased sensory nerve action potentials and MRI extensive transverse myelitis (spanning more than 2 vertebral seg-
may show increased hyperintensity of T2 weighted images in the pos- ments) and anti-aquaporin-4 (NMO-IgG) antibodies. More recently, the
terior columns [188,189]. term "NMO spectrum disorder" (NMOSD) has been used to describe a

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wider range of NMO positive neurologic conditions that share some serous morbidity occur. The challenge of diagnosing SS is further dis-
features of NMO but don't meet the criteria for the diagnosis of this cussed in the next section.
disorder [201,202]. Given the fact that aquaporin-4 antibodies were
only described in 2004, it is conceivable that some of the past cases of
3. Challenge of diagnosis
SS described as MS mimics may actually be attributed to NMO or
NMOSD.
Estimates on the prevalence of Sjögren's syndrome in various po-
pulations differ widely [220–223]. With a recent estimated prevalence
2.3.36. Autonomic nervous system involvement
between 2.2 and 10.3 cases per 10,000 in the U.S. [224], primary
Autonomic nervous system dysfunction (dysautonomia) in SS can
Sjögren's Syndrome should no longer be designated as a rare disorder
manifest as persistent tachycardia, orthostatic hypotension, GI dysmo-
(i.e. affecting < 200,000 people) according to the U.S. Rare Diseases
tility, bladder dysfunction, and hypohydrosis/anhidrosis
Act of 20021. Despite this observation, Sjögren's continues to present a
[122,189,192]. The prevalence of dysautonomia is highly variable,
common diagnostic challenge for practicing clinicians. The average lag
reported in 3-50% of SS depending on how it was defined and assessed
between symptom onset and diagnosis is reported by the Sjögren's
[189]. Potential etiologies include cholinergic neurotransmission
Syndrome Foundation to be 2.8 years2.
blockade by cytokines or autoantibodies, T-cell infiltration, and auto-
The challenge of diagnosing Sjögren's is multifaceted, and may in-
nomic nerve destruction [189].
volve both patient and provider factors. Onset of symptoms is often
insidious and non-specific and, there are currently no universally ac-
2.3.37. Cognitive dysfunction
cepted diagnostic criteria. Providers unfamiliar with the wide spectrum
Neuropsychological impairment a.k.a. "brain fog" is a common
of extra-glandular presentations and associated conditions may not
complaint among SS sufferers and characterized by difficulty with short
consider Sjögren's syndrome as a potential diagnosis in an individual
term memory, focus, concentration and mental clarity. The pathogen-
without dry eyes or dry mouth. However, sicca symptoms are not al-
esis is poorly understood. It may be idiopathic or related to one or more
ways present at the time of diagnosis. This scenario is particularly
secondary causes including anxiety/depression, chronic pain, non-
common among individuals who present with a neurological manifes-
restorative sleep, vitamin deficiencies, hypothyroidism or medication
tation of the disease [191]. Moreover, recent data have shown sig-
side effects. The self-reported prevalence in a recent survey of SS pa-
nificant rates of under-referral to relevant subspecialists even if the
tients was 53% [203]. Cognitive dysfunction can occasionally be the
patient presents with typical sicca symptoms [225]. Even when char-
presenting manifestation of the disease [204]. Neuropsychological
acteristic glandular and extra-glandular symptoms are absent, SS can
testing is the most helpful means to characterize the nature and degree
still occasionally be present. Further evaluation should also be con-
of impairment in patients with persistent or disabling symptoms. In-
sidered if incidental imaging findings suggest the diagnosis. This last
terestingly, discrepancies sometimes exist between patient reported
scenario may be particularly problematic due to the fact that imaging in
complaints of memory loss and the findings of objective tests
SS has been a relatively under-represented topic in the rheumatology
[191,205].
literature.
The results of neuropsychological testing vary among different SS
patient groups and have proven difficult to interpret across studies. This
may relate to various factors including small sample size, lack of uni- 4. Importance of correct diagnosis
form diagnostic criteria, different instruments used and varying efforts
to control for confounding variables that could potentially influence The ability to correctly diagnose Sjögren's syndrome is a skill that
study results such as age, medication use, depression, poor sleep and has important implications regarding patients’ quality of life, as well as
chronic pain. The most frequent abnormalities reported to date include: the overall morbidity associated with the disease. Although no large
deficits with verbal memory, verbal processing, language skills, atten- randomized controlled trials to date have identified a pharmacologic
tion, concentration and executive functioning [205–215]. Magnetic intervention that effectively alters the course of the disease, sympto-
resonance imaging of the brain in SS patients with cognitive dysfunc- matic management and monitoring tools are available that should be
tion can be normal or reveal findings of cerebral atrophy or white offered to every patient diagnosed with SS. Clinical practice guidelines
matter changes [208,216–219]. are now available to guide this process [226–234].
Frank dementia is uncommon in SS but has occasionally been re-
ported [204]. Therefore, any individual who presents with severe and/
4.1. Health-related quality of life
or progressive cognitive dysfunction, especially when associated with
other neurological signs and symptoms should be evaluated for central
The negative impact of primary Sjögren’s syndrome on patients’
nervous system Sjögren's. One study also reported that patients who
perceived health-related quality of life has well been documented
score multiple domains below the fifth percentile on neuropsycholo-
[235,236]. Based on conclusions from a recent large therapeutic trial,
gical testing are also at high risk for this complication [204].
patient-reported intensity of global dryness, pain and fatigue were
stronger predictors of patients’ poor quality of life than systemic ac-
2.4. Conclusions
tivity as measured by a physician [237]. This observation provides an
easily identifiable treatment opportunity for clinicians [226].
In summary, Sjögren's syndrome can cause a myriad of signs and
Notably, the above study used two validated tools, the EULAR
symptoms that can affect virtually any organ system. The clinical
Sjögren’s Syndrome Patient Reported Index (ESSPRI) and EULAR
manifestations may arise from multiple mechanisms including exocrine
Sjögren’s Syndrome Disease Activity Index (ESSDAI), to objectively
gland dysfunction, lymphocytic infiltration of other organs, associated
measure patient-reported outcomes and systemic disease activity, re-
autoimmune diseases, immune dysregulation and other coincidental
spectively [238]. Although developed as outcome measures for re-
comorbidities such as fibromyalgia. A comprehensive treatment plan
search, these scoring instruments could also potentially be used in
necessitates an understanding of the entire spectrum of disease espe-
clinical practice for therapeutic monitoring of patients with established
cially, common SS-related problems. A complete history and physical
SS.
examination including periodic clinical and laboratory re-assessment
for internal organ involvement, lymphomas and other complications
should help clinicians identify pertinent patient problems earlier in the 1
Rare Diseases Act of 2002, Public Law 107-280 – November 6, 2002.
2
course and initiate treatment before irreversible organ damage and/or www.sjogren’s.org. January 27, 2019.

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4.2. Associated autoimmune diseases, hematologic and lymphoproliferative Table 1

disorders Sicca signs and symptoms in primary Sjögren’s syndrome.a
Signs and symptoms of dryness
Additional examples that emphasize the importance of a timely and Ocular
correct diagnosis in SS include the serious morbidity that may result
from associated autoimmune disorders and the occurrence of life • Bacterial keratitis
• Blepharitis
threatening extra-glandular manifestations such as interstitial lung
• Conjunctivitis
disease or lymphomas.
• Corneal ulceration
Statistics from long-term outcome studies suggest that up to 71% of • Corneal vascularization and opacification
patients with primary SS develop at least one of the above problems • Decreased visual acuity
• Eye fatigue
during the disease course. Autoimmune thyroid disease is most fre-
• Erythema
quently observed among the autoimmune diseases associated with SS
but celiac disease, primary biliary cirrhosis, chronic active autoimmune
• Photosensitivity
Oral
hepatitis, myasthenia gravis and pernicious anemia also occur. Extra-
glandular manifestations and/or associated autoimmune conditions are • Adherence of food to the mucosa
• Angular cheilitis
most frequently observed among females as well as those with anti-
• Candida infection
SSA/ SSB antibody positivity, cryoglobulins and hematologic abnorm-
• Difficulties in speaking or eating
alities [239,240]. • Difficulty with dentures
Hematologic abnormalities are a common finding in patients with • Disappearance of the usual pooling of saliva in the floor of the mouth
• Dry and glazed oral mucosa
• Dysphagia
primary Sjögren's Syndrome and may include hypergammaglobuli-
nemia (37%), monoclonal gammopathy of undetermined significance
• Erythematous changes of the hard palate
(MGUS) (10%) or hypogammaglobulinemia (5%) [239]. Patients with • Fine wrinkles in the oral mucosa
MGUS must be closely monitored for the development of multiple • Local infection
myeloma and/or lymphomas, and individuals with hypogammaglobu- • Partial or complete depapillation of the tongue
• Periodontal disease
linemia may develop recurrent infections during the course of the dis-
• Red tongue with atrophic papillae
ease [241]. Significant hematologic abnormalities often occur relatively
• Soreness
late in the disease and are also associated with the presence of anti- • Surface of the tongue red and lobulated
SSA/SSB [239]. • Tooth decay
Other
The most important hematologic complication of primary Sjögren's
syndrome is the development of non-Hodgkin’s B-cell lymphomas
• Chronic, nonproductive cough
which affect 5-10% of patients and typically occurs 10-15 years fol- • Cutaneous dryness
lowing diagnosis [239,242]. In some patients this may be explained by • Difficulty swallowing
the overexpression of B-cell activating factor (BAFF) and a mutation in • Dysphagia
• Dyspareunia
the tumor suppressor gene, TNFAIP3 a.k.a A20 that results in un-
• Persistent hoarseness
controlled B cell proliferation and survival [243,244].The most
• Pruritis in the outer ear and ear canal
common type of lymphoma affecting Sjögren's patients is a low-grade • Vaginal pruritis
marginal zone B-cell lymphoma of the mucosa-associated lymphoid
a
tissue (MALT) type, followed by diffuse large B-cell lymphoma. Lym- Adopted from [231].
phomas typically present in the parotid glands, but can also affect the
submandibular glands, as well as extra-nodal sites including MALT glands are discovered serendipitously during evaluation for other pro-
lymphomas of the stomach, lungs, liver, spleen and orbit [245]. Among blems (e.g. CT or MRI for neck mass). The proportion of individuals
the major salivary glands, predilection for the parotid gland is likely presenting with some form of sicca syndrome is estimated at 80-85%
attributable to its unique feature of having embedded lymphoid tissue [231,245]. A list of signs and symptoms suggestive of dryness observed
within the parenchyma of the gland, a result of late parotid en- in primary Sjögren's is provided in Table 1 [231]. The prevalence of
capsulation in embryonic development [246]. A significantly increased extra-glandular manifestations as the initial presentation of SS from a
incidence of non-Hodgkin’s B-cell lymphoma has been observed among review by the EULAR-SS Task Force in 2016 is summarized in Table 2
men with SS as well as patients with cutaneous vasculitis, persistent [231].
salivary glandular swelling, low serum complement C4 levels and
mixed monoclonal cryoglobulinemia [239,247]. More recently, the list 6. Classification criteria
of risk factors for lymphoma has further expanded to include CD4
lymphopenia, rheumatoid factor positivity, lymphadenopathy, spleno- In recent years, several useful sets of classification criteria have
megaly, an ESSDAI score > 5, a salivary gland biopsy showing a focus been developed to standardize the case definition of SS for patient
score > 3/ 4 mm2 or the presence of ectopic germinal centers within enrollment in clinical trials and other research studies. Although not
the biopsy [248]. intended for diagnostic purposes, these criteria also provide a frame-
work upon which further diagnostic testing for SS can be based. Today
5. Clinical presentation the most commonly recognized criteria are the 2002 American-
European Consensus Group (AECG) criteria by Vitali et al. [249], the
The spectrum of clinical presentations among patients with primary 2012 classification criteria of the Sjögren's International Collaborative
Sjögren's ranges from sicca syndrome (derived from the Latin siccus, Clinical Alliance (SICCA) by Shiboski et. al. [250] also known as the
meaning dry) to systemic (extra-glandular) involvement. Interestingly, American College of Rheumatology (ACR)- SICCA criteria, and, more
sicca symptoms may be minimal or absent in this latter group at the recently, the 2016 ACR-European League Against Rheumatism (EULAR)
time of initial presentation. Additionally, patients who undergo further criteria (Table 3) [251].
evaluation for abnormal serologies (e.g. antinuclear antibody, rheu- Different criteria sets are still being utilized in different parts of the
matoid factor positivity), often drawn because of vague symptoms, will world and all have their respective advantages and disadvantages. All
sometimes have SS as the final diagnosis. Finally, Sjögren's is occa- utilize the same definition of a positive labial minor salivary gland
sionally suspected when imaging abnormalities of the major salivary biopsy (i.e. focal lymphocytic sialadenitis with a focus score > 1 /4

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Table 2 recent versions.

Extra-glandular/systemic presenting manifestations of Sjögren's.a The 2002 criteria also allow the use of key symptoms for classifi-
Organ-specific involvement Definition Prevalence (%) cation as SS and offer the largest menu of diagnostic tests from which to
choose. These criteria also provide a case definition for both primary SS
Cutaneous (i.e. SS that occurs without an associated connective tissue disease) and
Clinical 77
• Annular
secondary SS (i.e. occurs in association with another connective tissue
erythema Cutaneous ESSDAI 64
• Purpura/ ulcers moderate/ high 75
disorder e.g. rheumatoid arthritis). The 2012 criteria recommend
• Raynaud phenomenon
Joints
Clinical classification based solely on results of objective tests, offer the greatest
flexibility for autoantibody testing and advocate a more sensitive vital
Articular ESSDAI low 76 dye staining technique (combination fluorescein/lissamine green) to
• Arthralgia Articular ESSDAI 60
• Arthritis
Neurologic
moderate/ high
look for ocular surface damage.
The 2016 ACR-EULAR criteria represent a hybrid model of the two
Clinical/ EMG 46 earlier versions and have been endorsed by both professional organi-
• Axonal polyneuropathy Clinical/ EMG 64 zations to emphasize their importance. This version has a reported
• Ganglionopathy Clinical/ EMG 60
• Mononeuritis
87.4% sensitivity and 95.4% specificity for classifying primary Sjögren's
multiplex Cerebral MRI 60
• MS-like disease MRI 58
Syndrome when compared to physician diagnosis as the reference
• Myelitis EMG/ cutaneous biopsy 80 standard [252]. Interestingly, the 2016 archetype only endorses the use
• Small fiber neuropathy of anti-SSA positivity as serologic proof of autoimmunity (see below).
Pulmonary This model also offers the greatest flexibility for dry eye testing in-
Pulmonary CT 22
cluding use of 3 different vital dyes (rose bengal, fluorescein, lissamine
• Interstitial lung disease Ultrasound 55
• Pulmonary
hypertension
arterial green, or combination staining with fluorescein/lissamine green) and 2
different scoring systems [253,254] depending on which dye(s) are
Renal used. However, when the combination of fluorescein/lissamine green is
Renal biopsy 28
• Glomerulonephritis
utilized, the threshold for a positive result on a 0-12 scale (Ocular
Clinical/ ultrasound/ 25
• Interstitial cystitis biopsy
Surface Staining score) (OSS) was increased from > 3 (recommended
in 2012) to > 5 (now recommended in 2016). An OSS of 5 using
ESSDAI = EULAR Sjögren’s Syndrome Disease Activity Index; EMG = elec- fluorescein/lissamine green also equates to a Van Bijsterveld score of
tromyography > 4 on a 0-9 scale (recommended in 2002) using a single vital dye such
a
Adopted from [231]. as rose bengal.
A further description of diagnostic testing for SS is outlined below.
Table 3
2016 ACR-EULAR classification criteria for Sjögren’s1
7. Diagnostic evaluation
Inclusions

• anyone with dry eyes or dry mouth as defined by the 2002 criteria
Unfortunately, at the present time, there are no diagnostic tests that
• anyone with at least 1 extra-glandular manifestation as defined by
the ESSDAI questionnaire
have a high enough sensitivity and specificity to be used as stand-alone
diagnostic studies in SS. Therefore, a comprehensive evaluation with
Test Item Weight assessment of multiple parameters is recommended.
+ lip biopsy (FS > 1 / 4mm2) 3
Anti-SSA (Ro)+ 3
OSS2 > 5 (Van Bijsterfeld3 > 4)- 1 eye 1 7.1. Ocular assessment
Schirmer’s (without topical anesthesia) < 5mm/5 1
min.- 1 eye
Unstimulated whole mouth salivary flow < 0.1 ml/ 1 Every patient with suspected SS should undergo a thorough ex-
min amination by a cornea specialist or other eye care provider with ex-
POSITIVE SCORE FOR SS > 4 pertise in this area. The evaluation of dry eyes should include an un-
1. A positive biopsy is defined as focal lymphocytic sialadenitis with a focus score
anesthetized Schirmer’s test to quantify tear production. A value > 10
> 1/ 4 mm2 tissue surface area.
2. Ocular surface staining score (0-12 scale) for dry eyes using fluorescein/ mm wetting of the testing strip/ 5 minutes is considered normal and a
lissamine green. result < 5 mm/5 minutes is highly suggestive of Sjögren's dry eyes.
3. Van Bijsterveld score (0-9 scale) for dry eyes utilizing any vital dye Another complementary test for dry eyes is ocular surface staining with
Exclusions: prior head & neck irradiation, active hepatitis C infection (confirmation vital dyes (i.e. rose bengal, fluorescein, lissamine green) to evaluate for
by PCR), graft vs. host disease, acquired immune deficiency syndrome, sarcoidosis,
corneal and/or conjunctival epithelial damage [253,254]. Since fluor-
amyloidosis, IgG4-related disease.
escein typically reveals defects in the cornea but not the conjunctiva,
1. Adopted from [251]. combination staining with fluorescein and lissamine green (most sen-
2. Scale 0-12 [254]. sitive way to document conjunctival abnormalities) has now become
3. Scale 0-9 [253]. the procedure of choice for ocular surface assessment [254]. An Ocular
Surface Staining Score (OSS) > 3 and, later, > 5 on a 0-12 scale was
mm2 tissue) but also permit classification as SS without performing a lip considered clinically significant as per the Whitcher scoring [254]
biopsy if other parameters are satisfied. Additionally, all of the afore- system referenced in the 2012 and 2016 classification criteria, respec-
mentioned criteria facilitate classification of SS based entirely on ob- tively. Rose bengal staining may be used as an alternate method to
jective tests and endorse a case definition that does not absolutely re- examine the eye surface but has recently fallen out of favor because it
quire the presence of sicca symptoms; thus, the identification of SS is may aggravate stinging and burning sensations in patients with dry
possible in patients who lack sicca symptoms. Differences arise, how- sensitive eyes. However, a Van Bijsterveld score > 4 with rose bengal
ever, from varying opinions regarding the importance of including sicca staining on a 0-9 scale [253] would satisfy the ocular component of
symptoms in classification criteria for SS, recommendations for auto- both the 2002 and 2016 criteria. In addition to the above studies, in-
antibody testing and, testing for the evaluation of dry eyes and as- spection of the eyelids by slit lamp is recommended to look for signs of
sessment of salivary gland involvement (Table 4). For example, salivary meibomian gland dysfunction which causes evaporative dry eye and
gland imaging was included in the 2002 model but omitted from more further contributes to ocular discomfort.

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Table 4
Comparison of classification criteria for Sjögren's.
2002 AECG 2012 ACR-SICCA 2016 ACR-EULAR

2 2
Definition of positive biopsy Focal lymphocytic sialadenitis FS > 1/ 4 mm Focal lymphocytic sialadenitis FS > 1/ 4 mm Focal lymphocytic sialadenitis FS > 1/ 4
mm2
Sialometry Whole mouth salivary flow < 0.1ml/min. No Whole mouth salivary flow < 0.1ml/
min.
Inclusion of symptoms Yes No No
Salivary scintigraphy No No
Imaging Sialography
Serologic proof of autoimmunity Anti-SSA and/or SSB Anti-SSA and/or SSB Or +RF(any titer) and Anti-SSA
+ANA > 1:320
Dry eye tests Schirmer's < 5 mm/5 min. Combination vital dye staining OSS > 3 Schirmer's < 5 mm/5 min.
Or Or
Single vital dye staining Van Bijsterveld > 4 Single vital dye staining Van Bijsterveld
> 4
Or Combination vital dye staining OSS
> 5
Required for classification as SS 3 objective tests Or 4 of 6 (objective tests and 2 of 3 objective tests > 4 of 9 points
symptoms)

7.2. Evaluation of salivary gland involvement patient receives an intravenous injection of Tc-99m pertechnetate
(150 μCi/Kg) and is scanned for 60 minutes in the anterior Water's
7.2.1. Sialometry view. Maximal isotope uptake by the major salivary glands occurs
Salivary flow (sialometry) can be easily measured in the office by within the first 30 minutes and is followed by the spontaneous secretion
calculation of a whole mouth unstimulated salivary flow rate. This is of the isotope into the oral cavity through Stenson's and Wharton's
accomplished by measuring a patient’s salivary expectorant over 5-15 ducts. A gustatory stimulus (lemon drops) is administered in the final
minutes, and dividing by the collection time. A score of ≤0.1mL/min 15 minutes of the procedure to examine stimulated function and, all of
meets inclusion for the 2016 ACR-EULAR Classification Criteria where the activity in the major glands essentially drops out and appears in the
expert opinion assigned it equal weight to a positive Ocular Staining oral cavity. Regions of interest can also be drawn around the parotids,
Score and abnormal Schirmer’s test [251]. It is also included in the submandibulars, oral cavity and scalp to generate background cor-
2002 AECG Classification Criteria along with abnormal scintigraphy rected time activity curves (not shown) to look for differences in
and parotid sialography, as one of three diagnostic tests that can be function between the 4 visualized major salivary glands. In Sjögren's
used to demonstrate the salivary component of SS [249]. This contrasts syndrome defects in all 3 phases of salivary gland function have been
sharply with the 2012 ACR-SICCA Criteria in which the only accepted observed [260]. Thus, the procedure's ability to distinguish uptake
proof of oral involvement was limited to a positive labial salivary gland failure from secretory failure may be a useful asset in guiding clinical
biopsy in an attempt to improve criteria specificity [250]. management strategies and estimating outcomes.
Data have shown that the specificity of sialometry for Sjögren's
syndrome is enhanced when combined with a positive lip biopsy [255] 7.2.3. Histopathology
and/or with typical sialochemical changes [256], an analysis rarely Histopathologic assessment of the salivary glands plays an integral
done in a clinical setting. Higher sensitivity is also seen when sialo- role in the diagnosis of primary Sjögren’s syndrome. The procedure
metry of individual glands is performed rather than measurement of involves making a small incision in the lower lip to harvest at least 4-6
whole mouth salivary flow. For example, submandibular and sublingual minor salivary glands with a minimum surface area of 8 mm2
involvement tend to occur before the parotids are affected in early [261,262]. Hematoxylin and eosin staining help identify the presence of
Sjögren's [256]. Due to the need for specialized collection devices, dense mononuclear cell (mostly lymphocytic) aggregates. The finding
however, sialometry of individual glands is never performed in routine of foci of ≥50 mononuclear cells in a periductal or periacinal dis-
rheumatology practice. tribution, referred to as focal lymphocytic sialadenitis, is the most char-
acteristic biopsy feature of primary Sjögren’s syndrome with an 82.4%
7.2.2. Scintigraphy sensitivity and 82.6% specificity compared to other tests among pa-
Salivary scintigraphy provides an alternate means to noninvasively tients with diagnosed SS [263]. A focus score (FS) is calculated by di-
assess major salivary gland function [257], and represents one of the viding the number of foci by the total surface area of normal appearing
few imaging modalities ever included in any classification criteria tissue, then multiplying by 4. A focus of ≥1/ 4 mm2 of glandular tissue
[249]. In the United States this procedure is more widely available than is considered consistent with the salivary component of SS [262,264].
salivary gland ultrasonography and can be performed at any imaging The same definition of a positive biopsy has been included in all major
facility with nuclear medicine capability. However, since the protocol is classification criteria to date [249–251]
not yet standardized, the diagnostic and prognostic value of this study A large prospective cohort study, published in 2011, from the SICCA
depends on the imaging techniques used and the center that performs it international tissue registry provides the most recent validation for use
[257]. Therefore, cross comparisons of the sensitivity and specificity of of the current FS diagnostic threshold [262]. The study examined the
scintigraphy vs. other imaging modalities (e.g. ultrasound) for the di- relationship between phenotypic features of SS and lip biopsy results in
agnosis of SS are currently uninterpretable. The protocol referenced in 3 different patient groups: 1) focal lymphocytic sialadenitis with FS >
the 2002 American European Classification criteria measured isotope 1/ 4 mm2; 2) focal lymphocytic sialadenitis with FS < 1/ 4 mm2 and 3)
uptake into the major salivary glands (reflective of saliva formation) other histologic patterns like chronic non-specific sialadenitis or scler-
and spontaneous discharge in the resting state (i.e. between meals and osing sialadenitis. The results demonstrated a significantly (all
overnight) [258]. Since that time, newer protocols have also in- p < 0.0001) higher proportion of participants from group 1 (focal
corporated the administration of a secretagogue into the procedure in lymphocytic sialadenitis with FS > 1/ 4 mm2) vs. groups 2 and 3
order to measure stimulated function (i.e. after eating) [259,260]. among patients with positive serum anti-SSA/B antibodies (76%),
A typical scan for a normal individual is represented in Fig. 1. The rheumatoid factor (72%), antinuclear antibodies > 1:320 (72%),

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Fig. 1. Salivary scintigraphic images (5-minute

frames) in a healthy individual demonstrate normal
isotope uptake into the major salivary glands and
thyroid (frames 1-5); resting discharge through
Stenson's (black arrow) and Wharton's ducts (white
arrow) (frames 6-9) and stimulated discharge fol-
lowing secretagogue administration (frames 9-12).

keratoconjunctivitis sicca with OSS > 3 (50%) and unstimulated whole submandibular glands [271].
salivary flow rates ≤0.1mL/min (53%). No significant association was Studies assessing the ability of SGUS to correctly identify Sjögren’s
found between any pattern on biopsy and symptoms of dry mouth or versus other diagnostic modalities (including scintigraphy, sialography
dry eyes [262]. and salivary gland biopsy) have consistently demonstrated high speci-
Limitations of the labial minor salivary gland biopsy have been well- ficity and diagnostic accuracy [272–275]. A recent review reported that
documented and include insufficient glandular tissue for histologic most studies show a specificity ranging from 81.5%-98.7%. Sensitivity
examination (which can lead to overestimation of the focus score), in- values, however, show much greater variability and range from 48%-
correct histologic interpretation of the local inflammatory infiltrate, 91.4% [269]. Because of high specificity, ultrasound of the parotid and
and incorrect definition of a focus or lack of focus score quantification submandibular glands in recent years has gained popularity at many
[265]. In addition, there is substantial variability in the surgical ac- centers as a routine diagnostic study in patients with suspected SS
quisition and processing of the salivary gland tissue [266,267]. Given [276,277].
these differences, expert guidelines for the standardized use of salivary Limitations in determining the validity of ultrasound in SS stem
gland histopathology for clinical trials and future SS research were is- from an overall lack of uniformity between clinical studies, as well as
sued in 2017 following a 2-day workshop sponsored by the EULAR the multitude of imaging abnormalities found. Factors that have added
Sjögren's Syndrome Study Group [261]. to this heterogeneity include variation in study design, brands of ul-
trasound equipment, probe frequencies, scanning techniques, and dif-
ferent scoring systems used [277]. This has limited attempts to stan-
7.3. Imaging
dardize the procedure for inclusion in formal guidelines [277] and, thus
far, no current classification criteria include SGUS for assessment of
7.3.1. Salivary gland ultrasonography
salivary gland involvement [249–251]. However, this may change in
The use of salivary gland ultrasound (SGUS) in primary SS was first
the future as both ACR and EULAR have issued position statements on
explored in the late 1980’s [268]. Since then, ultrasound has been ex-
ultrasound in rheumatology that acknowledge the value of SGUS in SS
tensively studied as a diagnostic and monitoring tool in primary Sjög-
[276,278].
ren’s syndrome and is now considered the imaging modality of choice
Additionally, a 2017 study by Le Goff and colleagues assessed the
for the salivary glands [269,270]. The appeal of ultrasonography lies in
additional value that use of SGUS would add to existing classification
its non-invasive approach, low cost, and potential for easy and readily
criteria. They found that, when used as an alternative method for
accessible use. It is of a particular value in salivary gland assessment
documenting objective evidence of salivary gland involvement and
due to the superficial localization of the major salivary glands [270].
when given the same weight as unstimulated whole mouth salivary
Findings in pSS identified on static ultrasound images of the major
flow, Schirmer’s test and ocular staining scores, ultrasound may im-
salivary glands include heterogeneous parenchyma defined as hypo-
prove the sensitivity of the 2016 ACR/EULAR classification criteria for
and anechoic areas with or without hyperechoic bands. In addition, the
pSS. With physician diagnosis as the reference standard, the inclusion
presence of intra-glandular calcifications, abnormal lymph nodes, and
of SGUS increased sensitivity from 87.4% to 91.1% while specificity
the absence of visibility of the posterior border of the gland, particu-
remained high at 93.8%, compared to 95.4% without ultrasound [252].
larly for the submandibular glands, may also be seen. Notably, hyper-
This increase in sensitivity may allow additional patients with early
echoic bands may also be seen in normal individuals due to aging or
primary Sjögren’s syndrome who already have typical findings on
fibrosis of the glands, whereas heterogeneity within the gland is not a
salivary gland ultrasound, to be identified. The authors proposed that in
finding in normal glands. Among the different abnormalities seen, data
patients with SSA antibody positivity, a typical salivary gland ultra-
obtained by experts in SGUS have shown that the two most reliable
sound may provide sufficient evidence to reasonably forego a salivary
findings are echogenicity and homogeneity of both the parotid and

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gland biopsy. diagnostic algorithms require demonstration of the Sjögren's marker

autoantibodies, anti-SSA/SSB. The only exception to this view occurred
7.3.2. Magnetic resonance imaging in 2012 with publication of the ACR-SICCA classification criteria [34]
Findings on salivary gland MRI in Sjögren’s evolve according to the where it was suggested that the co-occurrence of RF (any titer) and
duration and extent of disease. Early findings include enlarged parotid ANA > 1:320 (any pattern) could be utilized as serologic proof of SS in
glands due to glandular edema from inflammation. As the disease the absence of anti-SSA/SSB positivity. This was based on findings from
progresses, lobular destruction may appear as small cystic changes as- a 2011 study described above that showed a significant association
sociated with fatty replacement [269]. Patients with longer chronicity between the characteristic histologic pattern of SS (focal lymphocytic
may show parotid gland atrophy and larger areas of cystic change in- sialadenitis with FS > 1/ 4 mm2) and RF and ANA positivity [262].
cluding cystic destruction or lymphoepithelial cysts (similar to those When present, the marker autoantibodies for SS may occur in one of
seen in HIV-associated salivary gland disease). Progression of fatty re- 3 different patterns: anti-SSA/SSB, anti-SSA alone or anti-SSB alone.
placement, as well as parenchymal calcifications and intra-parotid The first 2 patterns are common while the last one is rare. Both forms of
masses of lymph node aggregates can also be seen in advanced disease anti-SSA antibodies may occur together or separately in SS and re-
[246]. cognize either the Ro 52kD or the Ro 60kD antigens. The relative
In the evaluation of a salivary gland mass, including lymphoma, prevalence and clinical associations of each form of anti-SSA vary ac-
MRI can help determine infiltration of adjacent structures and may be cording to the assay methods used and the populations tested
used for local staging. However, it does not always reliably distinguish [282–284].
benign from malignant lesions in early disease [269]. Therefore, a Anti-SSB most frequently occurs with anti-SSA due to shared epi-
histologic diagnosis is required before treatment planning. An ultra- topes, and rarely occurs alone. In the SICCA registry, among 3297
sound-guided core needle biopsy under local anesthesia is preferable to participants tested for autoantibodies, isolated anti-SSB occurred in
fine needle aspiration and can easily be performed as an outpatient only 2% of cases. Despite its rarity, isolated anti-SSB was included in
procedure [279]. the 2002 and 2012 classification criteria as proof of autoimmunity for
SS. However, it was purposely excluded from the 2016 ACR-EULAR
7.3.3. Computed tomography criteria following a study by Baer and coworkers from the SICCA reg-
Imaging by CT is typically cheaper, faster, and often easier to obtain istry [285] that examined the phenotype of the above group with iso-
than MRI. However, exposure to ionizing radiation is a limitation that lated anti-SSB. The study showed that despite the equal occurrence of
should be considered, and may be a drawback to its use. Similar to MR sicca symptoms, the anti-SSB group bore little resemblance to patients
imaging, CT allows visualization of glandular enlargement due to in- who were anti-SSA or anti-SSA/SSB positive. The majority of lip biop-
flammation in primary Sjögren's syndrome. In addition, non-contrast sies (74%) performed in the anti-SSB group were also negative. It was
CT is particularly useful for the evaluation of sialolithiasis, a condition also observed that a change in autoantibody assay procedures during
that also may present with salivary gland swelling [280]. the registry from the initial Bio-Rad Autoimmune EIA (Bio-Rad, Her-
While MRI is superior for assessing the extent of infiltration by cules, CA) to a Bio-Rad Bioplex 2200 multiplex flow immunoassay
glandular tumors into surrounding tissues, CT can sometimes differ- created a 10-fold increase in the number of anti-SSB positive results.
entiate between benign and malignant masses based on blood perfusion This suggests that many of these results are false positives that arise as
patterns and/or the presence of bony erosions [281]. Nevertheless, an artifact of newer automated assay procedures.
histologic confirmation is still required. Prior studies have shown that anti-SSA may occur in 1.7-17.5% of
normal individuals depending on the assay procedures used and the
7.3.4. Sialography populations tested [284,286]. A Swedish registry and health-care bio-
Conventional sialography is a radiographic study that involves bank study also reported that anti-SSA and other autoantibodies may
cannulation of Stenson's or Wharton's duct and injection of water-so- appear in the blood of SS patients up to 20 years before the actual
luble iodinated contrast medium to visualize the anatomy of the ductal diagnosis [286]. Thus, the presence of an autoantibody (even anti-SSA)
system [269]. Typical changes in ductal architecture related to chronic as a stand-alone test is insufficient to confirm the diagnosis of SS
inflammation from Sjögren’s syndrome include alternating ductal ste- without objective evidence of dryness.
nosis and dilatation. However, due to problems related to its inva- A variety of other autoantibodies have been described in Sjögren's
siveness and radiation exposure, it is rarely used in clinical practice as recently reviewed [287,288]. At least 3 of these novel antibodies are
today except in cases of suspected ductal obstruction that cannot be commercially available: anti-salivary protein 1 (anti-SP-1), anti-car-
confirmed by other imaging modalities [269,270]. Like scintigraphy, bonic anhydrase 6 (anti-CA 6) and anti-parotid secretory protein (anti-
sialography was part of the 2002 AECG Sjögren’s classification criteria, PSP). These antibodies were discovered in the IL-14α transgenic mouse
but was not included in more recent criteria sets because of these issues. model of SS [289] and shown to be markers of early disease. They
Sialo-CT and MR sialography are alternative modalities to visualize appear in the blood of these animals before anti-SSA/SSB antibodies,
the ductal system. Although very expensive, MR sialography has the and before lymphocytic infiltration of the salivary glands occurs [290].
advantage of allowing better visualization of the parenchyma and small Anti-CA 6 and anti-PSP recognize proteins found in both murine and
ductal branches without radiation or contrast. However, because saliva human salivary glands. The biological function of the antigen re-
acts as the contrast agent in MR sialography, this may pose an issue in cognized by anti-SP-1 remains unknown. However, recent work de-
Sjögren’s patients with severe xerostomia [270]. monstrated shared epitopes with antigens found in human parotid
glands [291]. These novel murine autoantibodies have also been de-
7.4. Proof of autoimmunity tected in the non-obese diabetic mouse model of SS, in humans with
established SS who meet AECG criteria, in humans with SS who are
At the present time, documentation of autoimmunity through ser- biopsy positive but SSA/SSB negative, and in patients with idiopathic
ologic testing or demonstration of a positive labial minor salivary gland dry eyes and mouth of less than 2 years’ duration [290]. Anti-SP-1 may
biopsy (see histopathology) comprise the 2 most reliable means to also be a marker for secondary SS in patients with rheumatoid arthritis
distinguish between primary Sjögren's syndrome and other diseases that [291]. Despite these promising results, however, further studies in
cause sicca symptoms and salivary gland swelling. Antinuclear anti- larger patient cohorts including healthy controls, patients with other
bodies (ANA) and rheumatoid factor (RF) are the two most prevalent connective tissue disorders and SS patients at various stages of the
autoantibodies in SS but generally are not used for diagnosis or clas- disease are needed before this novel murine autoantibody panel can be
sification criteria due to lack of specificity [158,282]. Most criteria or regularly used in practice.

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7.5. Moving toward diagnostic criteria Sialadenitis may also result from a variety of infectious organisms
[297,298]. Individuals with acute HIV, and/ or hepatitis C infection
At the present time, due to the lack of universally accepted diag- may develop a clinical syndrome with dryness, swollen salivary glands
nostic criteria for SS, clinicians are frequently left scratching their heads and rheumatic symptoms that is almost indistinguishable from primary
and forced to use classification criteria by default to make a diagnosis. SS [299,300]. In addition to Sjögren's syndrome, other autoimmune
Although the differences between criteria can be confusing, they always inflammatory processes that can affect the salivary glands include IgG4
aim to satisfy 3 basic objectives. The first 2 goals are to demonstrate disease and sarcoidosis [301,302].
objective evidence of dry eyes and salivary gland involvement. The Determining the etiology of salivary gland disease can sometimes be
third involves proof of autoimmunity which helps differentiate SS from suggested on the basis of the patient’s clinical history and the physical
numerous other causes of dryness and salivary gland swelling as de- examination. Attention should be paid to the acuity of symptom onset,
scribed below. In a practical sense, given the high specificity (> 90%) presence of pain, presence of associated symptoms (such as a viral
of the aforementioned classification criteria, any patient who meets at prodrome) and whether one or both sides are affected. Sialolithiasis and
least one of them can be confidently diagnosed with SS. It must be bacterial sialadenitis are often painful and acutely affect the glands
remembered, however, that classification criteria frequently sacrifice unilaterally, whereas non-bacterial infectious or autoimmune causes of
sensitivity in favor of specificity. Therefore, in a clinical setting, any sialadenitis can present acutely or over a longer period of time, and
patient with a positive anti-SSA antibody or lip biopsy who demon- typically involve glands on both sides [246]. Additionally, patients with
strates objective evidence of dryness should also be diagnosed with salivary gland stones often develop swelling of the affected parotid
Sjögren's once other diseases or conditions that cause similar symptoms gland after chewing or eating. They may be aware of past episodes that
have been excluded. In doubtful cases, the physician's clinical judgment resulted in the passing of stones or gravel in the mouth when the
always remains the gold standard for diagnosis. Our current approach swelling subsided. Patients with bacterial sialadenitis may become
to diagnosing SS in patients with unexplained sicca symptoms or extra- febrile and develop erythema surrounding the involved site.
glandular manifestations in the clinical setting is outlined in Table 5. In addition to laboratory evaluation looking for specific etiologies,
imaging studies may further be able to aid in diagnosis. Unenhanced CT
is recommended as the diagnostic test of choice for evaluation of sali-
8. Differential diagnosis
vary gland stones given its improved sensitivity over radiography for
detecting calcifications, obstructing masses and associated in-
While we recognize the high degree of variability in the clinical
flammatory changes [246]. If additional imaging is necessary in the
presentations of Sjögren's syndrome, ranging from sicca symptoms to
absence of a visualized stone, MR sialography may be able to identify a
largely asymptomatic patients to individuals with severe organ-specific
previously missed calculus and provide an overview of the salivary
involvement and high systemic disease activity, a discussion about the
gland ductal anatomy as a whole. Salivary gland infections typically
differential diagnosis of SS for the purposes of this article will in-
appear as non-specific glandular enlargement and fat stranding, and
tentionally be limited to that which pertains to the salivary glands.
may have associated thickening of the superficial cervical fascia and
Medication-induced xerostomia remains the most common cause of
platysma muscle. Attention should be paid to look for the presence of an
the sicca syndrome, especially in the setting of polypharmacy
abscess or large calculus, particularly in the setting of a bacterial in-
[292,293]. Other diagnoses that should be considered in patients with
fection, as these may require additional treatment such as drainage or
dryness and/or salivary gland enlargement include sialolithiasis (cal-
surgical removal. HIV-associated salivary gland disease has a more
culus disease), sialadenosis (fatty infiltration) and chronic sialadenitis.
characteristic finding of benign lymphoepithelial cysts (BLECs) which
Sialadenosis, or sialosis, typically causes painless symmetric glandular
can cause gradual onset of painless bilateral salivary gland enlargement
enlargement with mild sicca symptoms and results from a variety of
[303]. Sarcoidosis affecting the salivary glands can manifest as granu-
causes including the metabolic syndrome, malnutrition, medications
lomatous lymph node aggregates which appear as nonspecific intra-
(e.g. chronic steroid use) and alcoholism [294,295]. Chronic sialade-
parotid masses, and IgG4 plasma cell infiltration appears as nonspecific
nitis is a scarring disorder of the salivary glands that can cause severe
homogeneous enhancement of an enlarged gland [246,301,302].
dryness and is frequently associated with osteoarthritis [296]. Patients
who undergo external beam irradiation for head and neck tumors, or
radioactive iodine treatment for Graves' disease or thyroid cancer may
9. Summary
also develop sicca symptoms and glandular swelling from obstruction.
The clinician is confronted with many challenges when evaluating a
Table 5
patient for possible Sjögren's syndrome. These include a wide spectrum
Clinical diagnosis of Sjögren's syndrome.
of clinical presentations, an expanding list of differential diagnoses,
1. Anti-SSA positivity or RFa + ANA (> 1:320)b positivity (choose 1) lack of universally accepted diagnostic criteria and a bewildering array
2. Positive lip biopsy (focal lymphocytic sialadenitis with FS > 1/4mm2)
of diagnostic studies and algorithms from which to choose. A focused
3. Objective evidence of dry eyes (any 1)
a) Abnormal Schirmer’s test ( < 10 mm/5 min) evaluation to document objective evidence of dry eyes, objective evi-
b) Any abnormal ocular surface staining using vital dyes (i.e. rose bengal, dence of salivary gland involvement and proof of autoimmunity is most
fluorescein, lissamine green) important. At the present time demonstration of anti-SSA positivity
4. Objective evidence of salivary gland involvement (any 1) and/or histologic involvement with focal lymphocytic sialadenitis and a
a) Abnormal whole mouth salivary flow rate (< 0.3 ml/min)c
b) Abnormal scintigraphy (defect in ≥ 1 of 3 phases of salivary gland function
focus score > 1/ 4 mm2 provide the most reliable means to distinguish
i.e. uptake, secretion, stimulated function) between SS and its various mimics. The recent development of new
c) Typical appearance on salivary gland ultrasonography classification criteria should facilitate more clinical trials in the future.
d) Typical appearance on CT/MRI of the major salivary glands The emergence of new diagnostic techniques including salivary gland
ultrasonography and the identification of novel biomarkers should
Diagnosis requires fulfillment of ≥ 3 of 4, and exclusion of prior head & neck
move the field forward and, hopefully, simplify diagnosis in the future.
irradiation, HIV, active hepatitis C infection (confirmation by PCR), graft vs.
host disease, acquired immune deficiency syndrome, sarcoidosis, amyloidosis, Understanding what SS is requires appreciation of the genetic, en-
IgG4-related disease. vironmental and immunological factors that contribute to its existence.
a
Any titer. The next section with discuss known genetic factors contributing to the
b
Any pattern. development of SS.
c
Abnormal result.

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10. Genetics is strongly correlated with high titers of anti-SSA and anti-SSB
[309,315,316]. The contribution of genetic risk variants to this sig-
10.1. Introduction nature has been supported by the identification of association with
multiple genes that are involved in IFN responses, including
Over the past several years, genetic studies in SS have greatly ex- interferon regulatory factor 5 (IRF5), signal transducer and acti-
panded from hypothesis-driven testing of candidate genes in relatively vator of transcription 4 (STAT4), interleukin 12A (IL12A) and 2′-5′
small sample sizes, to much larger unbiased genome-wide association oligoadenylate synthetase 1 (OAS1).
studies (GWAS) made possible by revolutionary advances in genotyping IRF5 is the strongest association identified to date outside the MHC
technologies. Evaluations in populations from European and Asian an- region. This transcription factor is responsive to signaling through toll-
cestry have confirmed previously recognized associations with HLA-DR like receptors (TLR) and the type I IFN receptor (IFNAR) to promote the
and -DQ alleles as well as established strong associations with multiple expression of anti-viral and pro-inflammatory proteins [317,318]. IRF5
new genetic risk loci [304]. An important caveat to the powerful GWAS is associated with SS in all ancestries evaluated to date, with the most
approach is that the variant most associated with increased risk of SS is significant association being found for a promoter region CGGGG in-
likely to be a marker for a linked causal allele that has yet to be de- sertion/deletion (indel) polymorphism [319–322]. A second in-
termined. Subsequent functional studies showing how the risk allele dependent effect has been identified in European-derived populations
alters biological function are required to establish the precise SS risk that results from a haplotype of linked variants spanning both IRF5 and
variant. However, we know that both innate and adaptive immune the neighboring gene, transportin 3 (TNPO3) [323]. A recent model
functions are clearly affected by various SS risk variants. Many of the SS suggests that within this haplotype, the risk allele confers increased
risk genes identified to date are involved in interferon, lymphocyte binding of the transcription factor ZBTB3 to the IRF5 promoter, re-
migration, cytokine and cytokine receptor function and various other sulting in upregulated IRF5 expression [324].
intracellular signaling pathways that are important in multiple immune STAT4 is a transcription factor that is activated by type I IFN, IL-12,
cell subsets. and IL-23 [320,325–327]. Additive effects between the major risk al-
leles in IRF5 and STAT4 have been reported [320,327]. IL12 is an im-
10.1.1. Antigen presentation and epithelial cell function munomodulatory cytokine primarily secreted by dendritic cells and
The strongest and most consistent genetic predisposition to SS is monocytes. Acting upstream of STAT 4, IL12 plays an important role in
driven by the Major Histocompatibility Complex (MHC) region that Th1 cell differentiation and production of IFN-γ by T cells and NK cells
harbors the human leucocyte antigen (HLA) genes. Associations have [328]. The IL12A gene encodes a p35 subunit that forms a heterodimer
been identified with different Class II alleles that vary by population with a p40 subunit encoded by IL12B [329]. The risk attributable to the
and serological status [305,306]. The -DR2 and -DR3 alleles at HLA- IL12A genes appears to be stronger in Europeans than in Asians [306].
DRB1 have consistently been associated in Caucasian populations OAS1 is a type I IFN-induced gene often directly observed as over-
[20,307]. Meta-analysis of 23 studies from diverse ethnic backgrounds expressed in the IFN signature. Interestingly, a risk variant has been
confirmed that significant risk was associated with HLA Class II alleles identified that alters splicing, and shifts expression of the p46 isoform
DRB1*03:01, DQA1*05:01, and DQB1*02:01 [308]. Another large-scale to alternative transcripts that lack translational response to type I IFN
study found two highly significant associations [309]. The first was stimulation. At the protein level, the risk variant of OAS1 is associated
with an extended 5 mega base (Mb) haplotype peaking at HLA-DQB1 with decreased OAS1 enzymatic activity and viral clearance [330].
but also including Class III and II, in addition to a second independent Furthermore, overexpression of OAS1 transcripts appears to be ampli-
association effect that was localized to a narrow region peaking at HLA- fied by presence of anti-SSA. The pathogenic mechanism for how this
DQA1. Associations with HLA-DRB1/HLA-DQA1 and HLA-DPB1 have variant contributes to SS is currently unclear.
been established in Han Chinese and other Asian SS patients [306,310].
In general, associations in the HLA region tend to be even stronger 10.1.3. Other innate immunity factors
when serological status is considered. For example, associations of anti- B-cell activating factor (BAFF/BlyS) is central to the crosstalk be-
SSA and/or anti-SSB production with DRB1*03 and DQB1*02 alleles or tween innate immunity and stimulation of autoreactive B cells. BAFF is
with heterozygosity for DQw1 and DQw2 alleles are exceptionally typically produced by monocytes, macrophages and dendritic cells.
strong [311]. Interestingly, multiple HLA genes on the extended 5 Mb However, in patients with SS, T and B cells can also produce BAFF as
haplotype were comprised of risk alleles that altered mRNA expression well as salivary epithelial cells [331]. The production of BAFF has been
levels, suggesting that the HLA region potentially confers risk through shown to be inducible by type I and II IFNs. Protein levels of BAFF are
multiple pathogenic mechanisms. The loci with expression differences increased in serum of SS patients compared to healthy controls, and are
revealed when subjects were stratified by genotype included Class II highly correlated with disease activity and titer of circulating auto-
HLA-DRB6, -DPB1, -DQA1 as well as Class I HLA-C and -A. antibodies [332–337]. Candidate gene studies of BAFF and BAFF-R
Further contribution of the MHC region to risk of SS has been re- support association of a haplotype consisting of four linked SNPs lo-
ported from a non-canonical MHC-linked locus that is independent of cated in the 5’ regulatory region of the BAFF gene in patients that are
the HLA associations. This locus encompasses the Class I polypeptide- positive for anti-SSA and anti-SSB. A different haplotype has also been
related sequence A (MICA) gene. MICA is a highly polymorphic gene associated with SS in patients with lymphoma compared to healthy
that is expressed in epithelial cells and encodes a stress-induced gly- controls [337,338].
coprotein recognized by the natural killer group 2D (NKG2D) receptor Cytotoxic natural killer (NK) lymphocytes play a critical role in
expressed on various subsets of CD4+ T cells, CD8+ T cells and natural innate immunity. Based on evidence for a potential role of NK cells
killer (NK) cells [312,313]. Strong association of the MICA*008 allele observed in animal models of sialadenitis, a candidate gene study of
with SS has been found in two European cohorts [314]. The risk allele is NCR3/NKp30 was performed that showed association of SS with pro-
associated with increased levels of stress-inducible MICA protein in moter SNPs. These findings support a potential role for NK cells through
serum and may contribute to shared pathogenic pathways involved in promoting an NKp30-dependent inflammatory state in salivary glands
reduced protection against cancer and autoimmunity. [339,340].

10.1.2. Interferon responses 10.1.4. B Lymphocyte function

Dysregulation of innate immunity has been demonstrated by studies Complex dysregulation of adaptive immune responses clearly con-
of salivary glands and peripheral blood from SS patients. Increased tributes to the pathogenesis of SS. Several genetic associations have
transcription of IFN-inducible genes, referred to as the “IFN signature”, been established for genes involved in B cell function. Two SNPs in

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Early B-cell factor 1 (EBF1), a key transcription factor involved in B cell be specific for Asians has been identified with killer cell lectin-like re-
development, are associated with SS and changes in expression levels of ceptor, subfamily G, Member 1 (KLRG1) [306]. KLRG1 is expressed in
EBF1 can lead to impairment of B cell development [323]. B cell peripheral blood NK cell and monocytes and binds to NF-kB complex
function in SS is also thought to be affected by variants in a promoter proteins in B cells. Associations with IKZF1 have been reported in two
with dual transcriptional control for both the FAM167A and the BLK (B studies [306,352]. IKZF1 is a transcription factor that regulates lym-
lymphocyte kinase) genes. Association at this locus was first found in a phocyte differentiation and interestingly, shares common interaction
candidate gene study of Swedish and Norwegian populations, and later partners with GTF2I that are involved in histone deacetylation
replicated in other European and Asian cohorts [306,352].
[309,319,320,323,325]. FAM167A and BLK are transcribed in opposite
directions from a common promoter, and interestingly, have expression 10.2. Conclusion
levels that are inversely correlated. FAM167A encodes DIORA-1, which
is highly expressed in the lung and may have a potential role in pul- In summary, large-scale genetic studies to date have been re-
monary involvement [341]. BLK plays a major role in B cell signaling markably successful in establishing associations that are convincing and
through activation of multiple nuclear transcription factors. Risk of SS lend insight into the complex etiology of SS in individuals of European
through reduced expression of BLK may lead to breaks in tolerance by and Asian origin. There are dozens of additional strong candidate genes
allowing autoreactive cells to escape depletion [323]. In addition, a that have shown suggestive levels of association for which follow-up
novel association of SS with a SNP located upstream of the coding re- studies are warranted. Ongoing studies are aimed at precisely localizing
gion of CXCR5 has been described [309]. Dysregulated expression of the causal variants within the regions thus far associated with SS, de-
CXCR5 has been shown in B cells from the periphery and in salivary termining biological consequences such as the effects on cellular
gland tissues [342,343]. The SS risk allele of CXCR5 correlates with functions and contribution to clinical manifestations, understanding
decreased expression of CXCR5 in peripheral blood B cells, low num- similarities and differences between the genetic architecture of various
bers of CXCR5+ peripheral blood B cells, and homing of CXCR5+ B racial populations, and identifying additional novel associations. The
cells to the minor salivary glands [344]. genetics of SS are substantially understudied compared to other sys-
The nuclear factor kappa-light-chain-enhancer of activated B cells temic autoimmune diseases and will require continued effort to develop
(NF-kB) protein complex is found in almost all eukaryotic cell types and a comprehensive understanding of the underlying risk factors. To ad-
has a central role in rapid regulation of transcriptional responses to vance the field further, continuing to apply powerful genetic and
harmful cellular stimuli. Chronically active NF-kB signaling is found in genomic tools to increased sample sizes will be critical for gaining the
numerous inflammatory diseases. Two genes that regulate NF-kB statistical power needed to identify additional associations and begin to
pathways have been associated with SS. Risk variants in tumor necrosis understand how these risk variants operate in various patient subsets.
factor-alpha-induced protein 3 (TNFAIP3) have been associated with
increased risk of lymphoma in SS [345], possibly through dysregulation 10.3. Immunological and cell biological aspects
of ubiquitination. TNFAIP3-interacting protein (TNIP1) has also been
associated with SS [346]. TNIP1 cooperates with TNFAIP3, which in Based on the extensive pathology and histology now accumulating
turn suppresses toll like receptor (TLR)-induced apoptosis by negatively from SS patient biopsies and tissues, there is a strong consensus that SS
regulating NF-kB [347,348]. To date, the precise cell types affected by syndrome is a systemic autoimmune disease. Nevertheless, confounding
dysregulated NF-kB signaling in SS are unclear but likely to be complex factors, such as viral infections, anti-cholinergic drugs, radiation
and work mechanistically through pathogenic alterations in TNF-in- therapy, aging and other systemic inflammatory diseases known to
duced apoptosis, TLR4 activation, or cytokine production. cause pathology very similar to SS, must be excluded from any final
diagnosis. This is not a simple task considering the widespread dis-
10.1.5. Chromosome X tribution in humans of hepatitis B, hepatitis C, HTLV-1, mumps and
Speculation on the cause of the remarkable gender disparity in SS CMV, or rheumatoid diseases, sarcoidosis, irradiation, and environ-
(14:1 female: male ratio) has included numerous factors including mental factors [353]. Confounding this even further is the fact that
anatomy, lifestyle, and sex hormones with very little data to directly organ damage can be demonstrated in the presence of (auto)antibodies,
support these hypotheses [349]. Recent studies of the X chromosome but absence of detectable T and B lymphocytes, not unlike what can be
have suggested that a viable alternative explanation is that the number seen in other autoimmune diseases, e.g., type 1 diabetes and rheuma-
of X chromosomes increases the likelihood of developing SS, potentially toid arthritis [354,355]. These data and observations, when considered
through a gene dosage mechanism. together, suggest that (a) loss of salivary and lacrimal gland function
Men with Klinefelter´s syndrome (47, XXY) have a similar risk of can occur prior to detection of lymphocyte infiltration in the glandular
developing SS as normal 46, XX women [349]. In addition, the esti- tissue, and (b) lymphocyte-directed killing of the target organ is not
mated prevalence of SS in women with 47, XXX is ∼2.9 times higher necessarily a major factor, at least in some patients, during the early
than that in those with 46, XX [350]. The coexistence of Turner syn- course of disease. However, it does appear that an adaptive immune
drome (45, X) with SS is very rare. In studies of rare aneuploidies, response is a major feature in the later stages of disease. Thus, critical
structural chromosomal aberrations resulting in partial triplications of questions remain in defining the mechanism(s) by which organ injury
the X chromosome (Xp11.4 ::pter) have been described in 3 patients occurs (Fig. 2).
with SS, suggesting that dosage-sensitive risk genes may be located The prevalence of autoantibodies, especially ANAs that are used to
within this chromosomal interval [351]. Numerous genes with a role in define SS as a disease entity, point directly to the importance of B
immunological processes serve as interesting candidates, however the lymphocytes in SS. However, both B lymphocytes and antibodies have
causal gene(s) that mediate this effect are as yet unclear. many immunological functions and it would be expected that this is the
case in SS as well. Studies in various autoimmune diseases have sug-
10.1.6. Associations in Asian populations gested that some autoantibodies, especially IgM autoantibodies, may be
Several genes appear to be associated in Asian populations that have utilized by the immune system to recognize damaged tissues and recruit
yet to be confirmed in other groups. In a GWAS of Han Chinese, a novel cells that participate in tissue repair [356,357]. If tissue inflammation is
association with a region spanning GTF2IRD1-GTF2I [310] was re- downregulated prior to loss of function in the targeted tissue, any overt
ported and later replicated in an independent GWAS of Taiwanese Han autoimmunity would most likely go un-noticed or un-diagnosed. Per-
Chinese SS females. The potential biological role for either of these haps what defines development of SS and other autoimmune diseases is
genes in SS pathogenesis is unclear. Another association that seems to the inability to control tissue inflammation, thereby establishing the

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Fig. 2. The adaptive immune response profile in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice. Concomitant with the loss of salivary flow rates, lymphocytic
foci appear within the periductal exocrine tissue of the glands. The early lymphocytic foci (LF) are generally a core of T cells surrounded by large accumulations of B
cells (photomicrograph). Global gene micro-arrays reveal a set of genes upregulated coordinate with the time of LF appearance, and these genes identify biological
functions (yellow highlighted text) that indicate: (a) antigenic peptides are being presented by antigen-presenting cells in a MHC class II manner, (b) the majority of T
cells are T-helper cells, (c) B cell receptors are being activated with concomitant Ig class switching, leading to B cell-mediated cytotoxicity, and (d) mast cells
apparently are activated and undergo degranulate. The overall consequence of the adaptive immune response is the loss of neural activity and secretion. The
connection between the immune response and the neural response, apparently linked functionally by chemokines, raises the question of whether the source of the
chemokines is the glandular tissue per se.

correct environment for this innate response to activate an adaptive for the disease may merely involve reversing the mechanism by which
immune response characterized in part by conversion of a normal low the disease was induced, undermining the relevance to treating human
affinity autoreactivity to a high affinity autoimmune response that (a) is disease. Lastly, animals often respond immunologically different than
capable of injuring self-tissue(s) (e.g., IgG autoantibody-mediated cy- humans to environmental challenges, thus not all observations made in
totoxicity) and (b) activating memory B and T cells less susceptible to animals are translatable to human disease. In any event, observations
growth inhibitory and apoptotic signals than primary lymphocytes made in animal models of SS need to be reassessed in SS patients, when
[358,359]. Similar to T1-diabetes and SLE, a subset of SS patients possible [363,364].
produces autoantibodies years before clinical disease becomes evident While several recently published reviews have described more than
[360,361], an observation that raises the possibility that these patients 30 mouse lines that have been used to study SS, the vast majority of
may be responding to an environmental challenge that could be con- these ‘models’ fail to exhibit critical manifestations of SS, i.e., loss of
trolled long-term prior to a breakthrough to an overt disease. All salivary and lacrimal glandular functions [363,365,366]. The first
normal individuals appear to produce autoantibodies, just not in the murine models used to study SS were mice being utilized to study SLE
titers, isotypes and affinities seen in patients with autoimmune diseases. [16]. The (NZB X NZW)F1 mouse, which develops features of SLE, was
It seems logical to assume that SS-susceptible individuals have a genetic important to identify genes involved in the pathogenesis [367], even
predisposition that fails to downregulate an innate and/or adaptive though these mice do not develop sicca symptoms naturally. However,
immune function to a specific environmental trigger(s). this mouse model can be induced to develop SS-like symptoms using
The importance of B cells and their products in SS has been strongly Toll-like receptor 3 (TLR3) agonist known to activate production of
supported by the work of Peck and colleagues in a mouse model of SS in type 1 interferons [368]. Similarly, the MRL/lpr mouse, which ex-
which silencing the Ig-mu gene resulted in the lack of mature B lym- presses a mutation in Fas and therefore in reality represents a model for
phocyte development and the subsequent lack of a SS-like disease de- human lymphoproliferative syndrome [369], has been used as a model
velopment [362]. However, as with human SS, it remains unknown if for SS. These mice develop lymphocytic infiltrations of salivary glands
the SS-like disease in these mice is the result of autoantibody produc- and produce anti-Ro antibodies, but they fail to develop either kera-
tion or another B cell function. The use of animal models in the study of toconjunctivitis sicca or loss of salivation [370].
SS has several caveats. On the plus side, animal models of spontaneous The first murine model identified to naturally develop salivary and
SS-like disease permit studies of the time course for disease-associated lacrimal gland dysfunction consistent with SS was the NOD mouse
pathophysiological changes, the influence of inducing specific genetic [371]. While these mice were shown to develop both a type 1 diabetes
changes on the disease process, and the outcome of therapeutic stra- (T1D) and SS-like disease, the two autoimmune diseases were shown to
tegies. Animals can be autopsied to assess the status of organs at specific result from different genetic regulation. Importantly, the T1D pheno-
stages of disease, especially during the preclinical stages which can type has been shown to involve more than 20 chromosomal regions
almost never be appreciated in SS patients. On the negative side, SS is a with a strong dependence on the major histocompatibility complex,
heterogeneous disease, therefore each animal model likely represents a whereas the SS-like phenotype is far more permissive, a feature that has
single form of disease that may be present in some, but not all patients. permitted separation of the two diseases [372,373]. This was first de-
In addition, depending on how an animal model is established, the cure monstrated in the NOD.B10Sn-H2b/J mouse derived by replacing the

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MHC locus of the NOD mouse with the MHC of the C57BL/6 strain. affinity autoreactivity to a high affinity memory response driven by
These recombinant inbred (RI) mice do not develop T1D, but continue various cytokines. Recent in-depth studies by Ambrus and colleagues
to develop SS-like disease characterized by lymphocytic infiltration of using an Interleukin-14 (IL-14) transgenic mouse model [394] have
the salivary and lacrimal glands, as well as pulmonary disease, renal shown that these mice not only develop features of SS seen in patients,
disease and autoantibodies [374,375]. Similarly, deleting Toll-2 from i.e., hypergammaglobulinemia, autoantibodies, loss of salivary gland
the NOD mouse genome eliminates T1D without affecting development function, lymphocytic infiltration of the submandibular and lacrimal
of SS [376], while blocking intracellular adhesion molecule-1 (ICAM-1) glands before the parotid glands, lymphocytic interstitial lung disease,
early in the course of the disease prevents the salivary gland in- and mild renal disease, but also develop large B cell lymphomas late in
flammation without affecting T1D [377], indicating the critical role of life. Except for early-stage loss of salivary gland function and lympho-
non-MHC genes in these two diseases. cytic infiltration of the submandibular and lacrimal glands, these ob-
These early observations indicating that SS-like pathology of the served pathological features, including B cell lymphomagenesis, could
NOD mouse was dependent on non-MHC genes led to work designed to be eliminated by deletion of marginal zone B cells, lymphotoxin or the
identify those genetic regions of the NOD mouse regulating onset of the Ifn1 receptor gene [395]. Essentially, a continuous production of IL-14
SS-like phenotype. Two genetic loci derived from the NOD strain, Idd3 appears to drive this abnormal memory B cell function by providing a
(renamed autoimmune exocrinopathy-1, or Aec1) located on chromo- long-term opportunity for B cell transformation. Interestingly, while
some 3 and Idd5 (renamed Aec2) located on chromosome 1, were MRL/lpr, (NZB x NZW) F1 and C57BL/6.NOD-Aec1Aec2 mice produce
identified and bred into the C57BL/6J mouse, a non-autoimmune par- IL-14 at high levels, studies of C57BL/6.NOD-Aec1Aec2 mice have
ental strain being used at that time for most genetic studies. The re- shown that mice downregulate IL14 production once its SS-like disease
sulting RI mouse strain, named C57BL/6.NOD-Aec1Aec2, failed to de- has matured, resulting in no B cell lymphomagenesis (Ambrus and
velop T1D, but demonstrated loss of salivary gland function prior to and Peck, unpublished data).
concomitant with lymphocytic infiltrations of the exocrine glands, lung A major characteristic of SS observed in patients is a severe hy-
and kidney tissues, plus B and T cell activation, as well as autoantibody pergammaglobulinemia. As with many other autoimmune diseases, the
and inflammatory cytokine productions [378,379]. Importantly, tem- appearance of autoantibodies to the targeted organs, in this case, sali-
poral genomic-wide microarray analyses of the salivary and lacrimal vary and lacrimal gland antigens, salivary gland protein-1, carbonic
glands from C57BL/6.NOD-Aec1Aec2 mice have defined the various anhydrase-6 and parotid secretory protein, can occur before clinical
genes and gene sets exhibiting differential activations during develop- disease [291] or even the detection of anti-nuclear autoantibodies like
ment and onset of the SS-like disease at the molecular level with results Ro used in disease diagnosis [396]. These observations have been
indicating a strong IFN-signature [380]. confirmed in both mouse models for SS as well as in patients
Identification of an IFN signature in the C57BL/6.NOD-Aec1Aec2 [397–399]. In fact, Scofield et al. [400] were able to generate these
mouse is not only in-line with studies in SS patients, but also suggestive autoantibodies via immunization of SS-non-susceptible BALB/c mice,
that the environmental trigger could be a virus [381–383]. Over several leading to decreased salivary gland flow rates and lymphocytic in-
decades, researcher have hypothesized that development of SS is in- filtrations of the salivary glands. While lymphocytes was noted, no la-
itiated by a viral infection of the salivary and/or lacrimal glands that crimal gland disease nor disease of the lungs, kidneys or lymph nodes
leads to the initial tissue injury that sets off the disease process in in- were noted [401]. Similarly, anti-muscarinic receptor 3 antibodies are
dividuals with the appropriate genetic background [384]. In a study by seen in a subgroup of patients with SS. T cells from C57Bl/6-M3R-/-
Ohyama et al. [385], C57BL/6-lpr-deficient mice (C57BL/6.lpr/lpr-/-) mice immunized with M3R peptides transferred into C57BL/6-Rag-1-/-
were infected with a murine cytomegalovirus. The mice not only de- mice caused decrease in salivary flow and infiltration of the salivary
veloped sialoadenitis that persisted even after the infection was cleared, glands with lymphocytes [402].
but also a chronic inflammation with T cells and high titers of anti-Ro Yet despite the clear role for inflammation in the pathophysiology of
antibodies. In a different approach, Peck and colleagues performed a Sjogren’s there has been a lack of correlation between salivary flow and
genetic analysis of the IFN-signature seen in C57BL/6.NOD-Aec1Aec2 infiltration and tissue damage within the gland. Many patients display
mice concluding that the IFN-signature per se indicated the in- low inflammation but substantial loss of gland activity [403]. Salivary
flammatory response was directed toward a dsRNA entity [386]. gland secretion is a complex process and involves the interaction of
However, the concept of a viral trigger for SS is far from being resolved. many proteins. In acinar cells, following stimulation by neuro-
Results from extensive studies of SS in both humans and murine transmitters cytosolic levels of calcium increases, which activates ion
models establish a firm basis for SS being an intriguing autoimmune channels that create an osmotic gradient and drives the movement of
disease, thus understanding the disease requires understanding the water through specific channels. Knockout mice for AQP5, NKCC1,
immune response against the salivary and lacrimal glands per se and IP3R types 2 and 3, matriptase, and the M3 and M1 muscarinic re-
the immunological involvement of other tissues such as the lungs and ceptors are all reported to have a decrease in saliva flow [404–408].
kidneys. Clearly many different cell types are involved. For example, in The interplay between the epithelia and the immune system adds a
patients with SS, increased expression of BAFF in epithelial cells has further layer of complexity because T-cell knockouts of IP3K, STIM1/
been proposed to be responsible for the abnormal activation of B cells STIM2, and ID3 and overexpression of IL-12, BAFF, and sTNFR1 are all
and survival of autoreactive B cells [387]. The BAFF transgenic mouse also reported to induce loss of gland function and may initiate it by
model develops a disease similar to human SS including a proliferative different pathways [335,409–413].
glomerulonephritis [388]. While these BAFF transgenic mice do not However, in the cases of inflammation within the gland there is
normally develop lymphoma, they do so if lacking the TNF-α gene increasing evidence for involvement of the epithelial cells [414,415].
[389]. Furthermore, BAFF transgenic mice lacking marginal zone B Salivary epithelial cells can act as nonprofessional antigen-presenting
cells fail to develop features of SS, even though they still develop glo- cells by releasing proinflammatory cytokines, chemokines, and costi-
merulonephritis [390], an observation that implies that MZB cells, mulatory molecules that contribute to the inflammatory response
which are capable of producing lymphotoxin [391], are critical for the [414,416]. A key function of the salivary epithelia is to act as a barrier
development of SS [392,393]. It also demonstrates that various clinical and loss of tight junction function is linked to the development of
features in an animal with systemic autoimmunity may not all have the chronic immune disease. In addition to allowing the introduction of
same pathogenesis. neoantigens, loss of barrier function could also redistribute apical and
As stated above, one of the most interesting hallmarks of SS is the basolateral components and disrupt the secretory machinery of the
high risk for B cell lymphomagenesis. One hypothesis for this phe- salivary gland [417]. This can be initiated in response to cytokines such
nomenon is that development of autoimmune disease converts low as TNF and IFN [418]. Redistribution of proteins important in release of

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secretory granules could be associated with the misdirected release of increased in the salivary glands of patients with SS compared to normal
exosomes towards the extracellular matrix rather than the lumen of the controls in microarray studies. When its expression is increased in the
gland and contribute to disease progression [419]. However, our un- salivary gland cells of C57BL/6 mice, loss of salivary gland function
derstanding of why these changes occur and their mechanism are lim- with an increase in infiltrating lymphocytes is noted [432]. In addition
ited. to its effect on salivary gland function, increase BMP6 is likely to affect
Apoptosis of the salivary epithelial cells has been proposed as a the activity of other cells in the gland, such as infiltrating lymphocytes
major component in the pathogenesis of Sjogren’s syndrome [420]. and bone marrow mesenchymal stem cells [433,434].
Dysregulated apoptosis in epithelial cells by cytokines is reported to In contrast, Protein kinase C-delta expression is reduced in lym-
trigger T-cell activation leading to the induction of Sjogren’s syndrome phocytes of patients with SS [435], but deletion of this gene in C57BL/6
associated autoantibodies [421]. Similarly, TLR3 and TLR9 activation mice results in lymphocytic infiltration of multiple organs, including
are also associated with apoptosis in salivary derived epithelial cells the salivary glands, resulting in hyposalivation [436]. Another protein
[422,423]. important in T cell receptor signalling is phosphatidylinositol-3- kinase
Autophagy is a dynamic cellular process initiated in response to (PI3K) [437]. Deletion of PI3K from T cells of C57BL/6 mice leads to
stress induced by hypoxia, starvation, and likely homeostasis and ER selective loss of lacrimal gland secretory function [409]. Lastly, another
stress response in salivary glands [424]. Because of the intense secre- molecule important for T cell receptor signalling is the inhibitor of
tory activity in the salivary gland there is likely high levels of ER stress differentiation-3 (Id3) protein. When deleted from C57BL/6 mice, these
and activation of the unfolded protein response. Autophagy plays a mice showed loss of both lacrimal gland and salivary gland function in
protective role and regulates cell death in cooperation with apoptosis. the absence of detectable lymphocyte infiltrations of the glands or
During autophagy, protein, organelles and cytoplasm become envel- production of either anti-Ro or anti-La antibodies [438].
oped within double membrane vesicles (i.e., autophagosomes) and are Overall, results from studies co-ordinately performed with SS pa-
subsequently degraded after fusion with lysosomes, then recycled to tients and appropriate mouse models exhibiting SS-like disease not only
maintain cellular metabolism. Failure to complete autophagy induces validate important concepts of SS pathology as an autoimmune process,
apoptosis and is associated with accumulating proteins such as phos- but also the use of animal models to identify potential molecular and
phorylated α-synuclein (α-syn) and amyloid-β, in diseases such as cellular processes currently not possible in human medicine. The var-
Alzheimer, Parkinson, and Huntington disease. The autophagy pathway ious mouse models for SS continue to provide increasing knowledge of
is upregulated in tissue from SS patients [424,425]. In salivary gland issues that were largely missed in studies looking exclusively at SS
cells, autophagy and apoptosis, are proposed to contribute to a redis- patients. These include the concepts that (a) loss of salivary and la-
tribution of Ro/SSA and La/SSB to the cell surface and presentation for crimal gland function may occur before or even without identifiable
autoantibody production [426]. However, the mechanism and triggers lymphocytic infiltration of the glands, even though lymphocytes most
for activation of these pathways is not clear but may be in response to likely participate in the pathophysiology of the disorder, (b) the innate
viral infection which is known to be modulated in epithelial cells in immune system is important in the pathophysiology of the disease and
response to virus infection [427]. Viruses such as hepatitis C virus, not simply the result of a disorder in the adaptive immune system in
which is associated with initiating Sjogren’s syndrome like symptoms which self-tolerance has been lost, (c) salivary and lacrimal gland injury
upon infection is reported to increase autophagic flux [428]. may occur via multiple different mechanisms that may not be the same
While much of the work on salivary gland epithelial cells has fo- in all patients, (d) autoantibodies and B lymphocytes are critical factors
cused on the role of the acinar cells there is likely a strong connection in the early stages of development and onset of SS pathophysiology, (e)
between acinar function and ductal integrity. Fluid section is initiated SS progresses through many stages of disease that apparently occur
by the acinar cells but this NaCl rich fluid is modified by the ductal cells over a course of many years in patients, a fact supported by molecular
which is essential for its biologic function. Damaged ducts will likely and cellular studies in the mouse models, (f) cytokines such as IFN, IL-
block the flow of proteins from the gland and could result in damaging 14, lymphotoxin and IL-17 may be variable at different stages of the
the acinar cells by the many digestive enzymes in saliva. A critical disease, thereby regulating the direction of disease onset, (g) despite the
ductal protein in this process is the chloride secreting channel cystic fact that SS has been shown to have a strong IFN signature and that
fibrosis transmembrane conductance regulator (CFTR). Confocal ima- there is considerable interest in viruses as an environmental trigger for
ging and western blots of NOD mice show reduced expression of CFTR. onset of SS [439,440], this concept remains an open question, and (h)
Treatment of mice with small molecule drugs that improve the activity events necessary for the progression of SS through its various stages,
or trafficking of CFTR or over expression of CFTR by gene transfer, including lymphomagenesis, will require further studies in animal
restored salivary gland activity and decrease inflammation and fibrosis models before headway is made in delineating the various subtypes of
in the tissue. This change in a ductal protein results in changed in acinar SS and subsequently understanding what patients within each subtype
cells including calcium signaling and expression of AQP5 [429]. are undergoing.
Other ductal proteins that sense increased Ca or ATP as a result of
injury are the Purinergic receptors. P2X7R is overexpressed in glands of 10.4. Initial approach and need for treatment
patients with pSS [430].This has been linked to the release of the
proinflammatory cytokine IL-1β and activation of the inflammasome Sjögren's syndrome is difficult to diagnose and equally challenging
complex. P2X7R stimulation in salivary acinar cells can result in de- to manage. No cure or agent able to induce remission exists. Presently,
polarization of the mitochondrial membrane and production of reactive therapeutic goals are targeted toward symptom palliation, prevention
oxygen species and cleavage and release of α-fodrin which maybe an of disease complications (especially in the eyes and mouth) and treat-
initiating event associated with pSS. Inhibition of P2X7 receptors can ment of serious and/or life-threatening systemic manifestations with
reduce the inflammation in the gland and associated exocrinopathy immunosuppressive therapy. The treatment algorithm should therefore
[431]. initially focus on the oral, ocular and systemic morbidities. Choice of
It is reasonable to assume that self-proteins aberrantly expressed in therapy depends upon the severity of symptoms, disease severity and
both SS patients and animal models with SS-like disease represent the degree of internal organ involvement.
targets for the immune response and are not merely coincidental ob- Patient surveys consistently identify sicca symptoms, fatigue, mus-
servations. Identifying these changes in expression are likely at the culoskeletal pain and cognitive dysfunction as the most prevalent and
center of the altered signalling network and immune imbalance asso- disabling symptoms in SS [41,441]. Two studies examined the impact
ciated with the autoimmunity. One such protein recently studied is of severe dry eye disease by utility assessment and documented utility
bone morphogenic protein-6 (BMP6), first noted to be selectively (patient perceived morbidity) values similar to those found in patients

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Table 6
Preservative free artificial tears.a
Product Active ingredients Notes

Bion® Tears (Alcon/Novartis) 0.1% Dextran 70; 0.3% hypromellose 2910

Blink® PF (Johnson & Johnson) 0.25% PEG 400
Clear Eyes® Pure Relief (Prestige) 0.25% glycerin Preservative free multi-dose bottle
FreshKote® Preservative Free (Focus Laboratories) 2.7% polyvinyl alcohol, 2.0% povidone Preservative free multidose bottle; stored behind pharmacy counter; also
contains glycerin
GenTeal® Tears (Alcon/Novartis) 0.1% Dextran 70; 0.3% hypromellose 2910
NanoTears® TF PF (Altaire) 0.4% PEG; 0.3% PEG
Oasis® Tears (Oasis Medical) 0.2% glycerin
Refresh Classic® (Allergan) 1.4% polyvinyl alcohol, 0.6% povidone
Refresh Optive® (Allergan) 0.5% CMC; 0.9% glycerin
Refresh Optive Advanced® (Allergan) 0.5% CMC, 1% glycerin, 0.5% polysorbate
80
Refresh Optive Mega-3® (Allergan) 0.5% CMC, 1% glycerin, 0.5% polysorbate Also contains castor oil and flaxseed
80
Refresh Optive Sensitive® (Allergan) 0.5% CMC, 0.9% glycerin
Refresh Plus® (Allergan) 0.5% CMC
Soothe® PF (Bausch & Lomb) 0.6% PPG, 0.6% glycerin
Systane® (Alcon/Novartis) 0.4% PEG 400; 0.3% PEG
Systane Ultra® PF (Alcon/Novartis) 0.4% PEG 400, 0.3% PPG
Theratears® PF (Akorn) 0.25% CMC

CMC=carboxymethylcellulose; PEG = polyethylene glycol; PPG = propylene glycol.

a
Not an exhaustive list.

with angina and/or on dialysis [442,443]. Additionally, in this parti- 10.5. Treatment of dry eyes
cular population, undiagnosed and/or untreated xerostomia and kera-
toconjunctivitis sicca (KCS) frequently result in devastating, costly The correlation between the severity of ocular symptoms and the
medical and dental complications including oral and ocular infections, results of objective tests for dry eyes is often poor [459,460]. Therefore,
accelerated caries, loss of dentition, corneal ulcers/perforations and regardless of symptom severity, every Sjögren’s patient should see a
visual impairment [444]. cornea or dry eye specialist at least once for a comprehensive evalua-
In the 1950s, Sjögren's syndrome was once described as "a chronic tion. This should include: 1) measurement of tear production; 2)
and relatively benign form of systemic lupus erythematosus" [445]. staining of the cornea with fluorescein and the conjunctiva with lissa-
However, in recent years, physician perceptions regarding the overall mine green to assess the degree of ocular surface damage; and 3) in-
morbidity associated with SS have dramatically changed. This aware- spection of the eyelids for signs of meibomian gland dysfunction
ness is further heightened by the recognition that SS is frequently (MGD). Although KCS in SS cannot be cured, effective therapies are
complicated by the development of non-Hodgkin’s B-cell lymphomas currently available to manage symptoms and prevent complications.
[69,446]. A study in Britain noted a much higher percentage of serious While SS is classically thought to cause decreased tear production or
internal organ involvement in lupus compared to SS, but also reported aqueous tear deficient dry eye, there is also evidence that many SS
that the overall level of functional disability in both disorders was the patients have significant MGD, also known as blepharitis, leading to
same [447]. At least 7 studies using various instruments have docu- evaporative dry eye as well ([38]. Although KCS is the most frequent
mented poor quality of life (QOL) (including oral health QOL) in SS ocular manifestation of SS, it is important to note that SS patients are
versus healthy controls [41,448–453], and QOL that is diminished to also at risk for other vision-threatening ocular complications such as
the same degree or worse compared to patients with rheumatoid ar- corneal melts, scleritis, and optic neuritis [31,461].
thritis [448,449] or fibromyalgia [449]. Recently, Foulks et al, in conjunction with the Sjögren’s Syndrome
Higher rates of unemployment [451,454] and increased health care Foundation, Inc. (SSF) published clinical practice guidelines for the
costs have also been observed in the SS population. In the United management of dry eye associated with SS ([30]. In that algorithm, the
Kingdom direct annual health care costs were found to be similar in treatment of KCS is approached in a step-wise fashion and patients are
individuals with primary Sjögren's syndrome and rheumatoid arthritis divided into those with or without MGD. Therapies are subsequently
but more than twice the annual health care costs of patient controls chosen based on the nature and severity (graded 1-4) of the disease and
[455]. Not surprisingly, SS patients have higher levels of caries, more tailored to the individual patient. To varying degrees, many SS patients
tooth extractions and higher dental (especially out of pocket) expenses suffer from both problems.
over a lifetime compared to the normal population [25,456]. In 2003-4, For patients with aqueous tear deficiency (level 1) modifications of
Sjögren's syndrome-specific language was formally incorporated into the environment (e.g. avoidance of windy or dry environments) and
the revised U.S. Social Security Administration disability guidelines activities of daily living can be helpful. However, if these measures are
[457]. inadequate, the first line therapy for dry eye should be lubrication with
In addition to the typical SS-related problems, the clinician also artificial tears in reusable bottles containing preservatives; these drops
must consider other comorbidities that are highly prevalent in SS and are dosed as needed to four times daily.
occur more frequently than expected by chance alone. These co- It is helpful to note that there are important differences between
morbidities include moderate to severe anxiety ( < 48%), depression artificial tears with or without preservatives. Preservatives in certain
( < 47%) and fibromyalgia ( < 47%) [41,73,74,214,448,457,458]. preparations de-stabilize the tear film and can be toxic to the ocular
These additional disorders can exacerbate many SS symptoms such as surface, especially if used frequently throughout the day. A general
fatigue, pain, dryness, and cognitive dysfunction and, thereby, add to rule-of-thumb is that patients with mild dry eye should not use any
the overall burden of illness and further complicate SS assessment and supplemental tears with preservatives more than 4 times a day.
management. The patient's psychosocial needs should also be addressed Sjögren’s patients with moderate-to-severe dry eye should be instructed
as part of the overall treatment plan. to only use preservative-free artificial tears (Table 6) which typically

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Table 7
Higher viscosity artificial tears.a
Product Preservatives? Active ingredients Notes

Blink® Gel Tears (AMO) Yes 0.25% PEG 400

GenTeal® Moderate Liquid Drops (Alcon/ Yes 0.1% Dextran 70; 0.2% glycerin; 0.3%
Novartis) hypromellose
Lacrisert® (Bausch & Lomb) No Prescription-only; dissolvable pellet inserted inside lower
eyelid
Oasis® Tears Plus (Oasis Medical) No 0.2% glycerin
Refresh Celluvisc® (Allergan) No 1% CMC
Refresh Liquigel® (Allergan) Yes 1% CMC
Refresh Optive® Gel Drops (Allergan) Yes 1% CMC; 0.9% glycerin
Systane® Gel Drops Yes 0.4% PEG 400; 0.3% PPG
TheraTears® Nighttime dry eye therapy (Akorn) No 1% CMC

CMC= carboxymethylcellulose; PEG = polyethylene glycol; PPG= propylene glycol.

a
Not an exhaustive list

come in single-use individual vials. topical cyclosporine and topical lifitegrast. Although not FDA approved
In general, thicker or more viscous artificial tear preparations for this indication, there is also some evidence that oral secretagogues,
(Table 7) stay on the ocular surface longer, but also tend to blur vision. such as pilocarpine and cevimeline, may be effective in alleviating dry
Since supplemental tears at best remain on the surface of the eye < 60 eye symptoms as well [469–471].
minutes, regular use is recommended to optimize treatment results. The use of oral omega 3 essential fatty acid supplements is also
Additionally, ocular gels or ointments are utilized at bedtime for longer mentioned in the treatment algorithm. However, a recent large, double-
lasting relief (Table 8). Another option for longer lasting relief is the blind, placebo-controlled, multi-center, randomized clinical trial found
preservative-free hydroxypropyl cellulose insert or Lacrisert® (Bausch & no benefit over placebo when using these supplements for the treatment
Lomb, Bridgewater, NJ) [462]. This insert is placed inside the lower of dry eye [472]. Once inflammation of the ocular surface is controlled,
eyelid by the patient and releases tears onto the ocular surface punctal occlusion of the openings to the tear ducts (puncta) using plugs
throughout the day as the pellet dissolves from body heat. or cautery can be helpful in conserving tears [473].
As dry eye worsens to a moderate severity level (level 2-3), patients Finally, for patients with severe (level 4) ocular surface disease,
often require additional therapies, which may include anti-in- additional therapies include the use of topical autologous serum drops
flammatory drops or oral prescription secretagogues. Topical steroids [474,475], partial closure of the interpalpebral fissure to reduce eva-
can be useful for short-term relief of KCS symptoms, although possible poration from the ocular surface, or large-diameter scleral contact
complications such as cataract formation, infection, and secondary lenses [476]. Patients with filaments or mucus strands on the surface of
glaucoma limit their long-term use [463,464]. A short two to three- the cornea (i.e. filamentary keratitis) may benefit from topical N-acet-
week course of topical steroids can be considered in select patients with ylcysteine drops, which can be obtained from a compounding phar-
dry eye flares. Topical 0.05% cyclosporine is thought to decrease in- macy. In the worst-case scenario, patients with severe (level 4) KCS may
flammation by several mechanisms including inhibition of T-lympho- also require systemic anti-inflammatory or immunosuppressive medi-
cyte activation [465,466]. The recommended treatment dose is 1 drop cations to control their ocular disease.
to each eye twice daily. The most common side effect is stinging upon For patients with MGD, the first-line treatment requires daily at-
instillation, which can be alleviated by refrigeration of the product, tention to eyelid hygiene with the use of warm compresses, eyelid
instillation 5 minutes after adding a drop of artificial tears, or the massage and scrubs. Warm compresses that utilize moist heat, such as a
concurrent use of a topical steroid for the first two weeks [467]. washcloth with warm tap water are preferred. A typical recommenda-
Recently, topical lifitegrast was approved by the FDA for the tion is to perform warm compresses twice a day with gentle lid massage
treatment of dry eye. Lifitegrast decreases inflammation by blocking the to encourage flow from the meibomian glands.
interaction of intercellular adhesion molecule ICAM-1 and lymphocyte In MGD, dryness develops because altered or diminished meibum
function associated antigen LFA-1. In four large, multi-center, rando- secretion causes dysfunction of the outer oily layer of the tear film and
mized clinical trials, lifitegrast was shown to be effective in improving predisposes to increased tear evaporation from the ocular surface. A
the signs and symptoms of dry eye [468]. Side effects include transient variety of lipid containing tears have been developed (Table 9) to ad-
ocular irritation and dysgeusia. Further studies are needed to explore dress this problem and may be used in addition to other tear substitutes.
the effectiveness of combination therapy such as the concomitant use of Additional measures for mild-moderate (level 2-3) MGD include the use

Table 8
Gels and artificial tear ointments.a
Formulation Product Active ingredients

Gels
GenTeal® Gel (Novartis) 0.3% hypromellose
Liposic® (Bausch & Lomb) carbomer
Systane® Lubricant Eye Gel (Alcon/Novartis) 0.3% hypromellose

Ointments
GenTeal® Nighttime Ointment (Alcon/Novartis) 3% mineral oil; 94% white petrolatum
Refresh Lacrilube® (Allergan) 42.5% mineral oil; 56.8% white petrolatum
Refresh PM® (Allergan) 42.5% mineral oil; 57.3% white petrolatum
Retaine PM® (OcuSoft) 20% mineral oil 80% white petrolatum
Soothe® Night Time Ointment (Bausch & Lomb) 20% mineral oil; 80% white petrolatum
Systane® Nighttime Ointment (Alcon/Novartis) 3% mineral oil; 94% white petrolatum

a
Not an exhaustive list.

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Table 9
Lipid-based artificial tears.
Product Preservatives? Active ingredients

Refresh Optive Advanced® (Allergan) No 1% glycerin, 0.5% CMC, 0.5% polysorbate 80

Retaine MGD® (OcuSoft) No 0.5% light mineral oil, 0.5% mineral oil
Soothe XP® (Bausch & Lomb) Yes 1% light mineral oil, 4.5% mineral oil
Systane Balance® (Alcon/Novartis) Yes 0.6% PPG, mineral oil
Systane Complete® (Alcon/Novartis) Yes 0.6% PPG; mineral oil
Tears Again® (OcuSoft) Yes Liposomal soy lecithin, vitamin A palmitate, vitamin E

of topical antibiotics, such as erythromycin 0.5% ophthalmic ointment lozenges (MightTeaFlow®) may actually stimulate salivary flow better
or azithromycin drops, as well as oral antibiotics such as doxycycline than a placebo [479]. The use of xylitol containing products is parti-
[30]. Patients with refractory MGD may be candidates for new treat- cularly encouraged as this agent is superior to other artificial sweet-
ments such as meibomian gland probing, intense pulsed light treatment, eners for caries prevention [480].
or continuous controlled thermal compression (Lipiflow System®). Systemic therapy with prescription secretagogues (pilocarpine, ce-
However, these treatments are often not covered by insurance and must vimeline) should be considered in any patient with significant symp-
be paid for out-of-pocket. Some of the other recommendations outlined toms, a history of oral complications, or at risk for oral complications
above for the treatment of aqueous tear deficiency are also applicable to due to an abnormally low whole mouth salivary flow rate (< 0.3 ml/
patients with MGD. min). Therapeutic success depends on residual salivary gland function
as reflected by results of sialometry or salivary scintigraphy. In placebo-
10.6. Treatment of oral manifestations controlled clinical trials pilocarpine at 20-30 mg daily in divided doses
was shown to significantly improve xerostomia, salivary flow, and other
Oropharyngeal dryness related to salivary dysfunction is an almost oral symptoms as well [470,481]. Major side effects included sweating
universal manifestation of SS and often severe enough to cause sig- and flushing. Cevimeline up to 90 mg/day in divided doses has shown
nificant QOL impairment. It may also cause difficulty with eating and similar benefits [482,483]. Although pilocarpine and cevimeline are
nutrition, dental complications, recurrent oral candidiasis and recurrent only FDA approved for the treatment of xerostomia associated with
salivary gland swelling. Sjögren’s syndrome, the available evidence suggests that these secre-
In all patients with xerostomia, it is important to identify and mi- tagogues may help other sicca symptoms as well [469–471,481–483]
tigate potential aggravating factors. Medications known to cause dry especially when regularly used at the maximum therapeutic doses. Both
mouth [292,477] should be discontinued or substituted whenever medications are best tolerated when starting with a low dose after
possible. Common offenders include anti-muscarinics, antidepressants meals and advancing slowly on a weekly basis to alleviate side effects
(especially tricyclics), anti-psychotics, antihistamines, diuretics, and until the target dose is achieved. Long-acting guaifenesin, an ex-
beta blockers. Lifestyle modifications can also be useful. Eating smaller, pectorant, at doses of 600 mg to 1200 mg by mouth twice daily seems to
more frequent meals can help stimulate salivary flow. To maintain oral stimulate increased secretions in the respiratory tract and can be useful
comfort, patients should take frequent, small sips of water or non-car- to treat dry nose, dry throat and dry lungs.
bonated sugar-free drinks (except citrus juices) throughout the day. There are also two devices (SalitronTM, SaliwellTM) FDA approved in
Patients should be encouraged to avoid low humidity conditions (such 1990 and 2017, respectively, that utilize electrical stimulation locally of
as air-conditioned environments during summer months) and use a the salivary glands to increase salivary secretion [484,485]. The Sali-
humidifier in the bedroom, especially during the fall and winter tron™ system involves a handheld probe that is placed on the dorsal
months. Avoiding the use of mouthwashes and rinses that contain al- tongue for 5 minutes three times daily; this device is no longer being
cohol or witch hazel is important as these can aggravate dryness and manufactured but is still in use. The Saliwell GenNarino™ has compo-
sometimes cause burning. Mouth breathing will typically exacerbate nents embedded into a removable mouthguard that can be controlled
nocturnal symptoms and can sometimes be corrected with proper with a remote. The Saliwell Crown™ involves permanent implantation
otorhinolaryngologic care. of a miniature electro-stimulating device near the third molar. Although
There are two approaches to xerostomia treatment in SS: saliva these devices cause no cholinergic side effects, their routine use has
replacement and stimulation of salivary flow with secretagogues. A been hampered by cost and insurance limitations.
variety of over-the-counter (OTC) artificial saliva products (Table 10) Meticulous dental hygiene is also critical to alleviate the risk of
can provide short term relief, but require continual use (e.g. 1-2 squirts dental complications, such as cracked teeth, loose fillings, accelerated
every hour while awake) for maximal benefit. Therefore, OTC saliva caries and loss of dentition. Use of an electric toothbrush, regular
substitutes are best utilized in provocative circumstances such as air flossing, and mouth rinsing with water after meals should be en-
travel, in place of water to alleviate nocturnal fluid ingestion, or as couraged. All patients with SS should see a dentist or oral medicine
adjunctive treatments to other therapies. Two prescription saliva sub- specialist every 3 to 6 months to help with the early diagnosis and
stitute powders (SalivaMAX™, NeutraSal™) are also FDA approved for treatment of dental caries. The 2017 SSF Clinical Practice Guidelines for
dry mouth. The powders are dissolved in water to create a super- oral management recommend application of topical fluoride in any
saturated calcium phosphate solution that is used as a gargle several form for all SS patients with dry mouth [233]. For example, one
times per day. These rinses have been studied in the oncology popu- strategy would be to brush 1.1% neutral NaF gel on the teeth after
lation and may alleviate mucositis as well as xerostomia [478]. Patients regular nighttime brushing at bedtime, leave on for 30 minutes, floss
should be counseled not to eat or drink within 15 minutes of use. Ad- and then rinse or swallow. Chlorhexidine varnish, gel, or rinses, as well
ditionally, moisturizing gels and oral lubricants, such as topical vitamin as non-fluoride re-mineralizing agents (e.g. MI Paste®) can be also
E oil or mineral oil, can also be applied to the tongue and inner cheeks considered as adjunctive therapies in patients with severe caries. Fi-
after meals and at night to soothe the mouth. nally, based on clinical experience and results in animal studies
For patients with mild symptoms, any gustatory or masticatory [486,487] efforts to increase salivary production through pharmaco-
stimulus can be used as a secretagogue to stimulate flow. A variety of logical measures are also mentioned in the guidelines and potentially
sugar-free lozenges, candies and gums are available to serve this pur- useful for caries prophylaxis as well.
pose (Table 11). Among OTC products, there is evidence that green tea Oral yeast infections are a common complication of severe

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Table 10
Artificial salivas and oral lubricants for dry mouth.a
Product Formulation Ingredients Manufacturer/Distributor

b
Aquaoral TM
Spray Oxidized glycerol triesters (TGO), silicon dioxide, aspartame, and artificial flavoring Mission Pharmacal Company, San
Antonio, TX
Biotene® Spray Purified water, glycerin, xylitol, PEG-60, hydrogenated castor oil, VP/PA copolymer, GlaxoSmithKline Consumer
flavor, sodium benzoate, xanthan gum, methylparaben, propylparaben, sodium Healthcare, L.P., Pittsburgh, PA
saccharin, cetylpyridinium chloride
Gel Glycerin, water, sorbitol, xylitol, carbomer, hydroxyethyl cellulose, sodium hydroxide
Entertainer’s SecretTM Spray Sodium carboxylmethylcellulose, potassium chloride, dibasic sodium phosphate, KLI Corporation, Carmel, IN
parabens, aloe vera gel, glycerin
GC Dry Mouth Gel Polyglycerol, pure water, sodium carboxymethylcellulose, carrageenan, sodium citrate, GC America, Inc, Alsip, IL
flavors, ethyl p-hydroxybenzoate
MEDActive® Patient- Gel Water, glycerin, xylitol, poloxamer 407, dimethicone, EDTA, flavor, potassium sorbate, MEDActive Oral Pharmaceuticals,
FriendlyTM Spray sodium saccharin, sucralose, xanthan gum LLC, Odessa, FL
Moi-Stir® Spray Water, glycerin, sodium carboxymethycellulose, methylparaben, potassium chloride, Kingswood Laboratories, Inc,
dibasic sodium phosphate, propylparaben, calcium chloride, sodium chloride, Indianapolis, IN
magnesium chloride, flavors
MouthKote® Spray Water, xylitol, sorbitol, Yerba Santa, citric acid, natural lemon-lime flavor, ascorbic acid, Parnell Pharmaceuticals, Inc. San
sodium benzoate, sodim saccharin Rafael, CA
b
NeutraSal® Rinse Dibasic sodium phosphate, monobasic sodium phosphate, calcium glycerophosphate, Invado Pharmaceuticals, LLC,
sodium chloride, sodium bicarbonate, silicon dioxide Pomona, NY
Oasis® Spray Lemon oil, ethyl cellulose polymer, zanthan gum, xylitol, sucralose, eucalyptus oil, Oasis Consumer Healthcare,
wintergreen oil, sodium bicarbonate, glycerol, zinc gluconate, thymol, calcium sulfate, Cleveland, OH
potassium phosphate dibasic
OraCoat XyliMelts® Dissolvable disc Xylitol, acacia gum, mild natural mint, cellulose gum, calcium carbonate, magnesium OraHealth, Bellevue, WA
stearate
Spry® Spray Purified water, xylitol, aloe vera, vegetable glycerin, spearmint flavor, calcium Xlear Inc, American Fork, UT
glycerophosphate, cellulose gum, grapefruit seed extract
b
SalivaMAX® Rinse Dibasic sodium phosphate rinse Forward Science, Stafford, TX
MightTeaFlow® Spray Deionized water, glycerin, xylitol, aloe vera leaf juice, jaborandi leaf extract, xanthan Camellix, LLC, Augusta, GA
gum, green tea extract, raspberry extract, resveratrol, vitamin D, ascorbic acid, zinc
gluconate, calcium bicarbonate, sodium fluoride, sodium bicarbonate, potassium sorbate
Rinse Deionized water, glycerin, xylitol, aloe vera leaf juice, jaborandi leaf extract, green tea
extract, raspberry extract, resveratrol, vitamin D, ascorbic acid, zinc gluconate, calcium
bicarbonate, sodium fluoride, disodium phosphate, sodium benzoate

a
Not an exhaustive list, adapted from the Sjogren’s Syndrome Foundation Product Directory.
b
Prescription required.

xerostomia in SS, with a prevalence of 74% found in one study [488]. above therapies to treat angular cheilitis. The use of secretagogues can
Chronic erythematous candidiasis, with physical exam findings of be useful in preventing recurrence [489].
atrophy of the filiform papillae, mucosal erythema, and/or angular About a third of SS patients will develop parotid or submandibular
cheilitis is typically seen, as opposed to classical thrush. Patients may gland swelling over the course of the disease. Proper treatment first
complain of glossodynia, stomatopyrosis or intolerance to spicy foods. requires accurate diagnosis with imaging by CT or MRI and, sometimes
Prolonged treatment with systemic antifungals is often required (e.g. a major salivary gland biopsy. In patients with confirmed Sjögren’s
fluconazole 100-200mg by mouth daily for 3 weeks). Local treatment syndrome, the differential diagnosis includes bacterial sialadenitis,
with clotrimazole lozenges or troches with small sips of water (e.g. 10 sialolithiasis, sialostenosis, inflammatory sialadenitis, sialadenosis,
mg 5x/day) for 3 weeks work better for patients with minimal salivary non-Hodgkin’s B-cell lymphoma (usually MALT) lymphoma, or other
flow. Topical clotrimazole cream can be used in conjunction with the tumors.

Table 11
Non-systemic oral secretagogues.a
MEDActive® Patient- Lozenges Water, glycerin, xylitol, poloxamer 407, dimethicone, EDTA, flavor, potassium sorbate, MEDActive Oral Pharmaceuticals,
FriendlyTM sodium saccharin, sucralose, xanthan gum LLC, Odessa, FL

MightTeaFlow® Lozenges Xylitol, sorbitol, natural flavors, green tea leaf extract, jaborandi leaf extract, acacia Camellix, LLC, Augusta, GA
gum, silicon dioxide, magnesium stearate, sucralose
Gum Xylitol, maltitol, gum base, natural and artificial flavors, glycerine, gum arabic, camellia
sinensis (green tea) leaf extract, artificial color, sucralose, jaborandi leaf extract, resinous
glaze, carnauba wax, and BHT (to maintain freshness)
OraMoistTM Time-Released Xylitol, polyvinylpyrrolidone, carbomer homopolymer type A, lemon flavor, citric acid, Quantum Health, Eugene, OR
Patch calcium carbonate, hydroxypropyl cellulose, triglyceride, sodium chloride, silicone
dioxide, magnesium stearate, annatto, glucose oxidase, lysozyme, lactoferrin
SaleseTM Lozenges Lemon oil, eucalyptus oil, wintergreen oil, thymol, xylitol, zinc gluconate, sodium Nuvora, Santa Clara, CA
bicarbonate, calcium sulfate, potassium phosphate, xanthan gum
SalivaSureTM Lozenges Xylitol, malic (apple) acid, dibasic calcium phosphate, sodium citrate dihydrate, stearate Scandinavian Formulas, Inc,
acid, citric acid, magnesium stearate, silica colloidal, sodium carboxy methyl cellulose Sellersville, PA
TM
Spry Gum Xylitol, gum base, natural spearmint oil, gum arabic, calcium carbonate, vegetable Xlear Inc, American Fork, UT
glycerin, soy lecithin, carnauba wax
XyliChew TM
Gum Xylitol, gum base, vegetable glycerin, natural fruit flavors, gum arabic, sunflower Nature’s Stance, Poway, CA
lecithin, and carnauba wax

a
Not an exhaustive list, adapted from the Sjogren’s Syndrome Foundation Product Directory.

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Acute episodes of unilateral glandular swelling associated with fa- dose (< 15 mg daily) short-term (< 1 month) corticosteroids can be
cial redness and/or fevers suggest bacterial sialadenitis until proven utilized as bridge therapy while trying to find a steroid sparing agent.
otherwise. An attempt should be made to culture secretions at the or- Leflunomide, sulfasalazine and azathioprine were deemed to have si-
ifice of Stenson’s or Wharton’s duct after milking the salivary gland. A milar efficacy as steroid sparing agents except in situations with evi-
recent systematic review recommended treatment with cephalosporins dence of other major organ involvement (e.g. interstitial lung disease)
or fluoroquinolones to cover Staphyloccous aureus, Viridans streptococci, where azathioprine is preferred to treat multi-system disease. Use of
and, less commonly, gram-negatives [490]; metronidazole would be cyclosporine to treat joint pain in SS was also mentioned. Treatment
added in rare situations when anaerobes are suspected. Episodic uni- with higher doses of corticosteroids or for longer periods of time should
lateral glandular swelling, particularly, after chewing or eating is often only be considered as the worst-case scenario for patients who have
due to sialolithiasis or sialostenosis with ductal obstruction due to failed multiple DMARDS with frequent attempts to taper as soon as
mucus plugs. These episodes can usually be managed supportively with possible while searching for alternative therapies. The CPG on the use
pain control, hot compresses, milking of the affected gland, and sucking of biological therapy in SS also mentioned the possibility of using TNF-
on sour candies. Patients are sometimes aware of passing gravel or sour α inhibitors for Sjögren’s patients who exhibit overlapping features
tasting mucus in the mouth when the swelling starts to subside. Re- with rheumatoid arthritis and/or the use of intravenous rituximab for
currences can be prevented by regular milking of the salivary glands patients with severe or treatment refractory extra-glandular manifes-
and the use of systemic secretagogues. In cases of persistent duct ob- tations including inflammatory polyarthritis.
struction, intervention with sialoendoscopy may be indicated. Inter-
mittent unilateral or bilateral salivary glandular (usually parotid) en- 10.7.3. Treatment of fatigue
largement that lasts for days may occur in SS due to inflammatory Patients with SS can have disabling fatigue, and, in fact, fatigue was
sialadenitis. Acute cases can be treated with a prednisone taper. shown to be the predominant predictor of poor general health and
Chronic cases can be treated with hydroxychloroquine or low-dose physical function in a 2009 cohort study that compared SS patients to
methotrexate [491]. In the case of sialadenosis, tapering of corticos- age and sex matched peer controls [41]. The mainstay of treatment for
teroids, if applicable, should be pursued and patients should be coun- fatigue in SS is participation in regular low-impact aerobic exercise and
seled on weight loss and screened for hyperlipidemia. Asymmetrical self-care measures [60]. This approach has proven successful in several
glandular enlargement, especially if nodular or hard, or persistent patient groups including those with lupus [493–495], rheumatoid ar-
swelling greater than 12 weeks in duration that is not responsive to thritis [496], multiple sclerosis [497] and SS [498]. The CPG working
treatment, should raise concern for possible neoplasm. A biopsy may be group also suggested the use of hydroxychloroquine in selected cases to
indicated to help confirm the diagnosis, particularly if there is concern treat fatigue despite lack of evidence from controlled trials. Ad-
about lymphoma. ditionally, the evaluation and treatment of co-morbidities that cause
fatigue in SS such as sleep disorders (e.g. obstructive sleep apnea),
10.7. Treatment of systemic manifestations depression, fibromyalgia, hypothyroidism, vitamin D deficiency, vi-
tamin B12 deficiency, metabolic disorders and anemia should also be
10.7.1. Practice guidelines development pursued.
As alluded to earlier, the first ever US clinical practice guidelines
(CPG) for management of the ocular, oral and rheumatologic/systemic 10.7.4. Treatment of renal manifestations
manifestations of SS were developed under the auspices of the Sjögren’s The most common renal manifestation of SS is chronic tubu-
Syndrome Foundation, Inc. and published beginning in 2015 [30,492]. lointerstitial nephritis. If there is evidence of severe or active interstitial
All working groups followed a highly rigorous process with guidance nephritis, treatment with high dose systemic corticosteroids (pre-
from major professional societies including the Institute of Medicine, dnisone 1 mg/kg/day up to 60 mg per day and then tapering) is rea-
American Academy of Ophthalmology, American Dental Association sonable [499]. If a steroid sparing agent is required due to disease re-
and the American College of Rheumatology. The principles of AGREE lapse upon steroid withdrawal, azathioprine [499] or mycophenolate
and GRADE methodology were utilized to construct evidence-based mofetil [500] have been used with success. Renal tubular acidosis
guidelines and/or CPG based on expert opinion when evidence was (RTA), especially Type I distal RTA, also occur in SS and are treated
insufficient. A modified Delphi process was used to achieve consensus with alkali to correct the acidemia and, when necessary, potassium for
among a multidisciplinary panel of experts and key stake holders before persistent hypokalemia. Glomerular involvement (e.g. membranopro-
the CPG were adopted. This process is ongoing, and guidelines will be liferative glomerulonephritis) is relatively uncommon and should raise
expanded and/or revised as new information becomes available. suspicion for concomitant SLE or cryoglobulinemic vasculitis. The
The initial rheumatology CPG focused on treatment of inflammatory treatment algorithms used for glomerulonephritis associated with lupus
musculoskeletal pain, fatigue and the use of biological therapy in SS. In or vasculitis should be followed.
the next 3 years, guidelines are planned for interstitial lung disease,
vasculitis, renal disease, central nervous system manifestations, per- 10.7.5. Treatment of interstitial lung disease
ipheral neuropathies and non-Hodgkin's B-cell lymphomas. Presently, Patients with Sjögren’s syndrome can develop non-specific inter-
however, standards of care for these other problems vary widely among stitial pneumonitis (NSIP), usual interstitial pneumonia (UIP), crypto-
different centers and clinical decisions are based on uncontrolled stu- genic organizing pneumonia (COP), lymphoid interstitial pneumonia
dies, small case series/reports or experience in treating similar pro- (LIP), and less commonly primary pulmonary lymphoma of the BALT
blems in other closely related disorders such as systemic lupus er- (bronchial associated lymphoid tissue) variety. Follicular bronchiolitis
ythematosus and rheumatoid arthritis. can be also be present, often co-existent with interstitial lung disease
(ILD). The treatment of ILD in SS depends on the severity of symptoms
10.7.2. Inflammatory musculoskeletal pain and effects on lung function. The course can be highly variable ranging
Arthralgias and myalgias are highly prevalent among individuals from spontaneous improvement and/or stabilization to progression and
with SS, and in some SS patient groups, inflammatory polyarthritis has death [501,502].
been observed in 15-33% [66,67]. The recently published rheuma- In asymptomatic or minimally symptomatic patients with imaging
tology CPG for treatment of inflammatory rheumatic pain [60] re- findings of interstitial lung disease but without significant abnormal-
commended the use of DMARDS in a step-wise approach with hydro- ities on pulmonary function tests, patients can be monitored closely in
xychloroquine as first line therapy followed by the initiation of lieu of starting active treatment. Monitoring may include repeat high-
methotrexate (either alone or in addition to hydroxychloroquine). Low resolution CT scans and pulmonary function testing every 6 to 12

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months. For symptomatic patients, or those with worsening pulmonary corticosteroids (e.g. 1 mg/kg/day) followed by the addition of a steroid
function over time, regardless of the pattern of involvement, treatment sparing agent (e.g. cyclophosphamide oral or IV) [191,195]. Aza-
with oral corticosteroids (e.g. prednisone 0.5–1 mg/kg/day) should be thioprine and methotrexate may be use as maintenance therapy or in
considered as first line therapy. Although there is no robust evidence to patients who develop toxicity with cyclophosphamide [195,196]. Al-
support this approach in SS, anecdotal reports from small case series though not useful for most SS-related neuropathies, IV rituximab
suggest benefit with stabilization of NSIP, COP, and LIP [502]. Among showed benefit in 11 of 17 patients enrolled in a prospective cohort
individuals with the idiopathic interstitial pneumonias, UIP patients registry study in France [513]. Promising results were observed in SS
have the worst prognosis and are least responsive to treatment; how- patients with cryoglobulinemia, vasculitis or both and, the SSF CPG on
ever, in SS this is not always the case [503]. When SS patients fail first use of biologics in SS also mention this therapeutic option [60].
line therapy, escalation of treatment with other immunosuppressive
therapy is recommended. There is limited data that support the use of 10.7.7. Treatment of central nervous system manifestations
azathioprine or mycophenolate mofetil as steroid sparing agents, ex- Central nervous system (CNS) involvement in SS is relatively un-
trapolated from small case series showing efficacy for ILD in SS and common but can be devastating. Patterns may be diffuse (e.g. seizures),
other connective tissue diseases [504,505]. More recently, a 2012 focal or multifocal [188,189,191]. Clinical presentations can mimic
registry study from France reported improvement in 6 of 8 patients with ischemic strokes, or the relapsing-remitting or primary progressive
SS-related ILD (patterns not specified) following treatment with in- forms of multiple sclerosis. Other causes of similar symptoms must al-
travenous rituximab [506]. Moreover, the use of rituximab as a steroid ways be excluded. A diagnostic and treatment algorithm similar to that
sparing agent for Sjögren’s "pulmonary disease" was also endorsed in used for systemic lupus is most frequently followed. Depending on
the SSF clinical practice guidelines on the use of biological therapy in symptom acuity and severity, treatments may include IV pulse corti-
SS [60]. Cyclophosphamide combined with prednisone was successfully costeroids for 3- 5 days, prednisone at 1 mg/kg/day with a slow taper,
used in one study of 14 SS patients with biopsy proven lung involve- azathioprine 1-2.5 mg/kg/day and oral or IV pulse cyclophosphamide.
ment (NSIP, COP, mixed patterns, follicular bronchiolitis) and may also Neuromyelitis optica (NMO) and its limited form, "NMO spectrum
be considered in treatment refractory cases [507]. disorder", both occur in SS and cause demyelinating disease in asso-
ciation with anti-aquaporin-4 (anti-NMO IgG) antibodies in the blood
10.7.6. Peripheral nervous system involvement [51]. In these instances, treatment algorithms as per current guidelines
The most common peripheral nervous system (PNS) manifestations for idiopathic NMO are followed [201]. Initial therapy includes IV pulse
of SS are small fiber sensory neuropathy and axonal sensory or sen- corticosteroids for 5 days followed by a steroid taper and/or therapeutic
sorimotor polyneuropathy, and occur as part of a much larger spectrum plasma exchange. This is followed by the use of IV rituximab, aza-
of PNS abnormalities that also includes sensory ataxic neuronopathy thioprine, or mycophenolate mofetil as steroid-sparing agents for
(sensory ganglionopathy), mononeuropathy multiplex, cranial neuro- maintenance therapy [514–516]. At the present time, however, it re-
pathies, autonomic neuropathies and radiculopathies [188,189]. mains unclear whether the prognosis of NMO in SS differs from that of
Treatment strategies depend on neuropathy type, severity of symptoms, the idiopathic form and whether or not the approach to treatment
rate of progression and effect on the overall functioning of the patient. should change when both disorders coexist.
The current standard of care is based entirely on retrospective case
series/reports, registry studies and expert opinion. 10.7.8. Treatment of anxiety and depression
Small fiber sensory peripheral neuropathy in SS can cause dys- Sjögren’s patients significantly benefit from treatment of con-
esthesias and allodynia in a length dependent and/or non-length de- comitant anxiety and/or depression since these comorbidities not only
pendent distribution. The first line treatment is aimed at symptom exacerbate common SS symptoms but also heighten patients' illness
management, using medications for neuropathic pain such as gaba- perceptions [517]. Many patients look well despite having a chronic
pentin, pregabalin, or serotonin-norepinephrine reuptake inhibitors autoimmune rheumatic disease and are therefore reluctant to voice
[508]. Tricyclic antidepressants, although helpful, should generally be their symptoms. They often receive little support from their spouses or
avoided as they are likely to exacerbate sicca symptoms. Intravenous families. Therefore, extensive education of patients and families on SS
immunoglobulin (IVIG) at a dose of 400 mg/kg/day over 5 days, as disease manifestations and treatments will often significantly reduce
reported in small case series, may provide additional relief to patients the psychosocial burden of living with a chronic illness. Acknowl-
with progressive or refractory symptoms [509–511]. edgment of the severity of SS symptoms by family members and other
Sjögren’s may also cause a rare but disabling sensory ataxic neu- healthcare providers is essential in order to enable Sjögren’s sufferers to
ronopathy related to "dorsal root ganglionitis" that causes loss of ki- accept their disease and move on. Every individual should be en-
nesthesia, proprioception and progressive difficulty with ambulation couraged to join the Sjögren’s Syndrome Foundation, Inc. (www.
and fine motor movements. Case series suggest benefit from corticos- sjogrens.org) or one of its local support groups in order to gain better
teroids and IVIG, as well as treatment with mycophenolate mofetil 2 g/ access to reliable health information, expand their support networks
day [194,511,512]. and take advantage of volunteer opportunities to "fight back" against
Axonal sensory and sensorimotor neuropathies affect large nerve their illness. The overreaching goal of treatment should be to gradually
fibers and cause paresthesia in the distal extremities in a symmetrical change the patient focus from illness to wellness.
distribution with or without muscle weakness. Patients with mild sen- For SS patients who require more aggressive treatment, a non-
sory symptoms are treated symptomatically like those with small-fiber pharmacologic approach is always preferred. Helpful measures may
neuropathies. Intravenous immunoglobulin as dosed above should be include counseling, cognitive–behavioral therapy, relaxation techni-
considered in patients with significant motor deficits or refractory and/ ques, regular exercise, increased exposure to sunlight, treatment of
or progressive symptoms [511]. insomnia or guided self-help programs [517,518]. For patients with
Vasculitic neuropathies occur in SS and typically present as mono- treatment refractory anxiety and/or depression, psychiatric consulta-
neuropathy multiplex or as painful asymmetric peripheral neuro- tion is necessary to optimize care. Psychoactive drugs with antic-
pathies; they frequently occur in association with cryoglobulinemia. holinergic side effects (e.g. alprazolam, amitriptyline) are best avoided
Patients may experience the acute or subacute onset of limb pain as- to prevent exacerbation of sicca symptoms. Medication choice should
sociated with paresthesias, dysesthesias and varying degrees of weak- also be considered in the context of other comorbidities (e.g. fi-
ness including wrist drop or foot drop. The evaluation should include an bromyalgia/chronic pain, insomnia). Patients should be treated with
assessment for vasculitis in other organs and exclusion of other causes. the lowest possible dose of psychotropic medication that will achieve
Treatment should be initiated rapidly with high dose IV and oral the desired therapeutic effect.

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10.7.9. Cognitive dysfunction procedures. Conversely, in patients with less severe disease manifesta-
SS sufferers frequently complain of "brain fog", a form of cognitive tions at low risk for flares off immunosuppressive, it is reasonable to
dysfunction characterized by short term memory loss, difficulty with briefly interrupt treatment in the perioperative setting, as long as this
focus and concentration and lack of mental clarity; this may interfere does not necessitate an increase in glucocorticoid use.
with normal activities and add to the overall disease burden Immunosuppressants can be held at least 1 week before surgery and
[204,209,441]. Treatment varies by cause. Vitamin B-12 deficiency and resumed 2 weeks later barring any unforeseen complications [527].
hypothyroidism can be easily corrected. All patients benefit from gen- Biological therapies should be held at least one dosing interval before
eral treatment measures including institution of an aerobic exercise elective surgery and are resumed 2 weeks later as well [527].
program (if medically permissible), improvement of sleep and treat-
ment of chronic pain. All centrally acting medications (e.g. gabapentin) 10.7.12. Provider instructions
should be discontinued or substituted, if possible. Patients should be In addition to risks of adrenal insufficiency related to chronic
screened for anxiety and depression, and treated as above. steroid use, providers should also consider the risks of mucosal and
Cognitive remediation therapy has been successfully used to im- dental damage in the perioperative setting. Whenever possible, the use
prove cognitive function in other groups with similar problems of anticholinergic medications should be avoided. For patients with
[519,520] and is now being employed in SS as a complementary severe Raynaud's and digital ischemia, non-operative areas can be
treatment to other measures. Training is individualized to help patients covered with blankets, operating room temperature increased, and in-
better deal with everyday situations and achieve greater autonomy in travenous solutions warmed to help protect against flares. To prevent
their social and/or professional lives. Depending on the deficit, training corneal erosions the eyes should be taped shut intraoperatively with an
can be utilized to restore deficient functions and/or develop novel ocular lubricant or gel. A humidifier should be added to the oxygen
strategies to process and organize information and tasks. rebreathing system to prevent further dryness. For SS patients with
Individuals with persistent and/or progressive cognitive dysfunction caries and/or broken teeth, a mouth guard is required during oro-en-
should undergo formal neuropsychological testing. Frank dementia dotracheal intubation to prevent further dental damage. Likewise, extra
may occur in SS, albeit rarely [204]. Patients with multiple domains lubricants should be used during intubation to protect dry friable mu-
below the fifth percentile on testing or who demonstrate other neuro- cosa.
logical signs and symptoms associated with cognitive dysfunction re- In the postoperative period the nurse may need to crush or cut oral
quire a more thorough evaluation for possible central nervous system medications for SS patients with severe dryness who may also have
SS, a manifestation that requires different therapy. dysphagia. Ideally, whenever possible, the patient should be positioned
upright before administration of oral medications and given a full glass
10.7.10. Perioperative management of water to drink. Dry foods such as crackers which are frequently given
Every SS patient who is planning to have elective surgery under to patients in the postoperative period should be avoided. The patient's
general anesthesia should meet with their rheumatologist about 3-4 regular routine for treatment of dry eyes and dry mouth should be re-
weeks ahead of time in order to make the necessary preparations for sumed as soon as possible after surgery.
perioperative care [521,522].
11. Conclusions
10.7.11. Patient instructions
All oils (e.g. vitamin E oil, fish oils, flaxseed oil) used for manage- In summary, the management of Sjögren’s syndrome presents the
ment of dry eyes and dry mouth as well as low-dose aspirin used for clinician with numerous complex challenges. A comprehensive assess-
Raynaud's should be discontinued 2 weeks preoperatively in order to ment by experienced providers is necessary to determine the level of
minimize bleeding risk. Copious amounts of artificial saliva, sugar-free morbidity associated with the ocular, oral and systemic manifestations
lozenges and preservative-free artificial tears can be utilized as tem- of SS. Treatment algorithms are influenced by disease and symptom
porary substitute therapies. Individuals on chronic steroids should un- severity as well as the degree of internal organ involvement. Clinical
dergo a fasting cortisol to determine the need for stress glucocorticoids practice guidelines are now available for management of kerato-
perioperatively. Ideally, corticosteroids in patients who are not adren- conjunctivitis sicca, meibomian gland dysfunction, caries prophylaxis,
ally insufficient should be discontinued or tapered to the lowest pos- treatment of fatigue and inflammatory musculoskeletal pain as well as
sible therapeutic dose preoperatively since the risk of postoperative the use of biological therapy in SS. The patient's psychosocial needs
infection in this patient subset is significantly increased [523–526]. should also be addressed in order to optimize care.
Patients should be counseled that most of their usual Sjögren’s pre-
scription and OTC treatments (e.g. pilocarpine tablets, cevimeline 11.1. Research and future treatment considerations
capsules, artificial tears, ocular lubricants, artificial saliva, etc.) will
likely be non-formulary and unavailable. Therefore, they should bring As outlined in this review, many areas of research are ongoing in SS.
these items to the hospital along with a schedule for routine adminis- Basic studies are evaluating the role of the innate and adaptive immune
tration and, request that their own SS-related medications be ad- systems as well as various non-immunological cell types in disease in-
ministered to them on a regular schedule in the postoperative period. itiation and progression. More attention is paid to the various stages of
Current recommendations from the American College of disease that can evolve in patients with SS. Genetic studies are helping
Rheumatology and Association of Hip and Knee Surgeons permit the to elucidate key players in disease pathophysiology. The contribution of
continuation of certain immunomodulatory or immunosuppressive disorders of both aerobic and anaerobic metabolism are being in-
therapies in the preoperative and postoperative periods [527]. These vestigated, as they are in other autoimmune diseases, such as SLE
include hydroxychloroquine, methotrexate, sulfasalazine and le- [128,528–533]. As these research areas progress, new forms of therapy
flunomide. are conceptualized and investigated in clinical studies. Some of the
Management decisions on continuation of stronger im- current investigations focus on cytokines and cell populations known to
munosuppressive therapies including azathioprine, mycophenolate, be abnormal in SS.
cyclosporine, tofacitinib and tacrolimus must be made on a case-by-case Interferon signature is a consistent finding in patients with SS,
basis following consideration of the procedure risk versus risk of disease however the role of type 1 and type II interferons may vary in different
flare and internal organ damage off therapy. In general, in patients with stages of SS [381,395,534,535]. Some open labeled studies have proved
severe disease and high risk of flares with medication interruptions, that IFN-α given at low dosage by the oral-mucosal route can sig-
therapy should be continued, especially in the case of low risk elective nificantly increase UWS flow in patients with primary Sjögren's

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