INTRODUCTION — Sjögren's syndrome (SS) is a chronic systemic autoimmune disorder characterized by lacrimal and salivary gland inflammation with resultant dysfunction. SS may occur alone (primary form) or in association with a second well-defined rheumatic disease (secondary form). The most common associated diseases are rheumatoid arthritis and systemic lupus erythematosus.
In primary and secondary SS, exocrine gland inflammation leads to dry eye and dry mouth [1,2]. These features, when confirmed by objective measures, are often referred to as keratoconjunctivitis sicca and salivary hypofunction, respectively. Marked glandular swelling may occur, and additional related ocular or oral features may be present, as may a wide variety of other disease manifestations [3]. The clinical manifestations of SS may be divided into the exocrine gland features and the extraglandular disease features, which can potentially affect numerous other organs [4].
The clinical manifestations of exocrine gland disease in SS will be reviewed here. The extraglandular manifestations and diagnosis and treatment of both sicca and extraglandular manifestations are discussed separately. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and "Diagnosis and classification of Sjögren's syndrome" and "Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome" and "Treatment of moderate to severe dry eye in Sjögren's syndrome" and "Overview of the management and prognosis of Sjögren's syndrome".)
PATHOGENESIS AND HISTOPATHOLOGY — The dry eye and dry mouth of Sjögren's syndrome (SS) are caused by immune-mediated inflammation directed against the exocrine glands of the eyes and mouth. The pathogenesis of SS is discussed in detail separately. (See "Pathogenesis of Sjögren's syndrome".)
Briefly, the histopathologic features of the exocrine disease include extensive lymphocytic infiltration, accompanied by glandular and ductal atrophy (image 1). Lymphocytic infiltrates are primarily located around the striated ducts, leading to periductal foci [5]. In some patients, these lymphocytic infiltrates are organized as ectopic lymphoid structures resembling secondary lymphoid organs, with segregation of T and B cells, presence of CD21+ follicular dendritic cell networks, and high endothelial venules [6]. Germinal centers are a defining histologic feature of these ectopic lymphoid structures and can be identified in approximately 4 percent of minor and 16 percent of parotid gland foci when assessed with immunohistochemical staining for B cell lymphoma 6 protein (Bcl6) [6-8].
Two other histopathologic features of the salivary gland are characteristic of SS. The first is the lymphoepithelial lesions, defined by the presence of B cells infiltrating the ductal epithelium and associated ductal epithelial hyperplasia [9-11]. These lymphoepithelial lesions are present in up to 93 percent of parotid gland biopsies compared with 20 to 33 percent of minor salivary gland biopsies [12]. The second feature is an increase in immunoglobulin (Ig) G+ and IgM+ plasma cells and a concomitant decrease in IgA+ plasma cells, relative to control biopsies. The finding of <70 percent IgA+ plasma cells has a specificity of 95 percent and sensitivity of 100 percent for SS in one study [13].
The histopathologic process in the major salivary glands is known as benign lymphoepithelial sialadenitis. In the minor salivary glands, it is known as focal lymphocytic sialadenitis and is defined by the presence of multiple aggregates of periductal lymphocytes in areas of gland not affected by interstitial fibrosis, ductal dilatation, and acinar atrophy. The presence of one or more such periductal lymphocytic aggregates, each containing 50 or more cells, per 4 mm2 of salivary gland tissue is one criterion for the classification of SS [7,14].
EPIDEMIOLOGY — Dry eye and dry mouth are each present in over 85 percent of patients with primary Sjögren's syndrome (SS) [15,16]; the exception is children, in whom recurrent parotitis is typically a more dominant symptom than sicca [17,18]. In addition, presentation with sicca symptoms may vary on the basis of ethnicity, being less common among Asian populations (defined as including persons having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent) [15]. In the vast majority of patients, dry eye and dry mouth symptoms are present in tandem at presentation [19].
Discrete extraglandular involvement is present in approximately a quarter of SS patients [20]. However, limb pain and fatigue are common symptoms and are sometimes attributed to systemic involvement. In patients with SS associated with another rheumatic disease, extraglandular involvement may differ when compared with those with SS alone [21,22], most likely due to the nonspecificity of the systemic features. For instance, a higher prevalence of interstitial lung disease was observed in patients with an overlap of SS with rheumatoid arthritis when compared with SS alone [23]. A higher prevalence of Raynaud phenomenon, arthritis, and central nervous system involvement was observed in a study of 26 patients with an overlap of SS with systemic lupus erythematosus, when compared with 86 patients with SS alone [24].
Extraglandular rather than sicca manifestations may be the presenting feature in approximately 5 to 20 percent of patients [25,26]. This has been reported particularly among patients with peripheral neuropathies and interstitial lung disease, in whom an evaluation may provide evidence for SS, even in the absence of sicca symptoms [27-29].
In a multicenter Spanish registry of 1580 patients with primary SS followed for a mean of 10.2 years, the following frequencies of clinical manifestations were observed [25]:
●Symptoms of dry eye and dry mouth were present in 96 to 97 percent of patients at baseline
●Abnormal ocular tests and parotid sialography were present in 86 to 88 percent
●Serious systemic disease involvement occurred in 13 percent
●Lymphoma developed in 4.9 percent
DRY EYE — Common ocular symptoms of dry eyes in patients with Sjögren's syndrome (SS) include irritation, grittiness, itching, a foreign body sensation, and blurry/changeable vision [3]. Findings include diminished tear flow, vital dye staining of devitalized conjunctival cells and punctate areas of exposed corneal epithelial stroma, and increased tear osmolarity. Dry eye in SS is largely caused by a reduction in the aqueous component of tears (table 1).
Meibomian gland dysfunction is also common in patients with SS, with a resultant increase in tear evaporation, compounding the diminished tear production [30,31]. Meibomian gland dysfunction in patients with SS and its management are described separately. (See "Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy", section on 'Potential harms' and "Treatment of moderate to severe dry eye in Sjögren's syndrome", section on 'Definition and general approach'.)
Vision-threatening complications from dry eye include corneal melting, ulceration, and perforation, but are fortunately uncommon.
Major features of dry eye in SS include:
●Symptoms – Dry eye usually presents insidiously over a period of several years. The symptoms vary and are often worse in the evening. Affected patients may complain of a "gritty" or "sandy" feeling in their eyes rather than "dryness."
Other symptoms include irritation, itching, photophobia, glare, blurred vision, and the accumulation of thick, rope-like strands (mucus filaments) at the inner canthus. Mucus filaments are particularly present upon awakening.
●Findings – Ophthalmologic examination may reveal one or more of the following findings (see "Diagnosis and classification of Sjögren's syndrome", section on 'Tests for dry eye'):
•Surface epithelial damage, as detected by lissamine green (figure 1) or Rose Bengal (picture 1) staining of the interpalpebral bulbar conjunctiva, especially on both the nasal and temporal sides
•Punctate epithelial erosions of the cornea, most often in the inferior aspect, as detected by fluorescein staining
•Evidence of reduced tear production, as detected by a Schirmer test
•Mucus filaments
•Dilation of the bulbar conjunctival vessels
•Dullness of the conjunctiva and cornea
•Rapid tear break-up time
Complications of dry eye include corneal ulceration and perforations, which rarely may cause corneal melt [32,33].
Additional ocular disorders unrelated to dry eye may occur [3]. These conditions, which are seen infrequently in patients with SS, include anterior and posterior uveitis [34], scleritis [33,35], and optic neuritis [36]. (See "Uveitis: Etiology, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of scleritis" and "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Neurologic manifestations of Sjögren's syndrome", section on 'Central nervous system disorders'.)
DRY MOUTH
Clinical features of dry mouth — Chronic salivary hypofunction in Sjögren's syndrome (SS) has a number of characteristic symptoms and oral findings. Patients with SS may complain directly of oral dryness (termed "xerostomia") or of complications such as dysphagia and adherence of food to buccal surfaces, describing difficulty eating and swallowing dry food, such as crackers, without drinking liquids. They may also report problems with dentures, changes in taste, and difficulty speaking continuously for long periods.
Signs of salivary hypofunction include lingual papillary atrophy and lobulation, dry lips, glassy appearance of the palatal oral mucosa, and absent sublingual salivary pooling (picture 2) [37]. Salivary hypofunction is associated with an increased rate of dental caries (picture 3) and often with a decrease in the sense of taste and a change in oral microbial flora, including an increase in oral candidiasis [38-40]. (See 'Complications of salivary hypofunction' below.)
Diagnostic testing for the evaluation of salivary hypofunction and the use of labial salivary gland biopsy for identification of histopathologic changes characteristic of SS are described in detail separately, as are the management of dry mouth in SS and strategies for the prevention of related complications. (See "Diagnosis and classification of Sjögren's syndrome", section on 'Diagnostic tests' and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome".)
Dry mouth is a common symptom in the population, particularly in older adults [41], but objective evidence of reduced salivary flow is less frequent in healthy older individuals than in patients with SS [42]. Other causes of dry mouth include a number of drugs and other conditions and systemic disorders (table 1). (See "Diagnosis and classification of Sjögren's syndrome", section on 'Differential diagnosis'.)
Complications of salivary hypofunction — Salivary hypofunction may result in a number of complications:
●Dental caries, which occur in up to 65 percent of patients, and primarily affect the cervical root and incisal surfaces of the teeth [43,44].
●Oral candidiasis, which may occur in over one-third of patients [45-47]. (See 'Oral candidiasis' below.)
●Other types of oral infections, such as bacterial infections of the major salivary glands (picture 4).
●Laryngotracheal reflux, which may lead to frequent throat clearing, cough, substernal pain, and nocturnal awakening that simulates panic attacks [48,49]. Laryngotracheal reflux in SS is the result of decreased salivary flow, the absence of the normal gastric acid buffer, and reflux of gastric acid into the esophagus and trachea.
●Chronic esophagitis, also due to impaired clearance of acid and lack of the buffering effects of saliva. (See "Pathophysiology of reflux esophagitis".)
●Weight loss, due to difficulty with chewing and deglutition.
●Nocturia, which results from attempts on the part of the patients to counter dry mouth by drinking copious volumes of fluids.
Oral candidiasis — Oral candidiasis is a common complication of SS; it may occur in over one-third of patients [45-47]. Symptoms include a painful mouth, sometimes with a burning sensation, and sensitivity to spicy or acidic foods [50]. Findings in SS patients with oral candidiasis are typically those of erythematous or chronic atrophic candidiasis, including diffuse or patchy erythema, typically affecting the hard palate [51].
The presentation of oral candidiasis in SS is in contrast with the typically fluffy white exudates that predominate in patients with human immunodeficiency virus or with immunosuppression due to chemotherapy. The tongue, buccal mucosa, palate, lips, and corners of the lips may be affected, and there may be loss of tongue papillae. Angular cheilitis and atrophic changes of the buccal mucosa are common manifestations in SS [46]. (See "Oropharyngeal candidiasis in adults", section on 'Clinical manifestations'.)
Oral candidiasis is often facilitated by the wearing of dentures ("denture stomatitis"), which may need to be removed to determine whether candidiasis is present and to assess the response to treatment [51]. Oral candidiasis is particularly frequent following antibiotic treatment or the use of glucocorticoids.
SALIVARY AND LACRIMAL GLAND ENLARGEMENT
Benign glandular enlargement — Salivary gland enlargement occurs in up to 50 percent of patients with Sjögren's syndrome (SS) at some point over the course of the disease [52] and is present in 20 to 30 percent of patients in cross-sectional studies [53-55]. It may either be unilateral or bilateral. The glands are usually firm, diffusely enlarged, and nontender. These changes are most obvious in the parotid glands, but the submandibular and other glands may be affected to the same degree (image 2 and image 1). Salivary gland enlargement may be either chronic or episodic, with swelling followed by reduction over a few weeks.
Recurrent, paroxysmal swelling of the submandibular and/or parotid glands is a characteristic feature of eosinophilic sialodochitis, a disease sometimes misdiagnosed as SS. The salivary gland swelling is often associated with itching over the gland and the formation of eosinophil-rich mucus plugs. Up to two-thirds of patients have associated atopy and peripheral blood eosinophilia [56,57].
Ultrasonography is the preferred imaging tool to determine whether there is salivary gland involvement, since it is non-irradiating and can be performed at the "bedside" in real-time by the clinician (see "Diagnosis and classification of Sjögren's syndrome", section on 'Salivary gland ultrasonography'). Hypoechoic foci are the most characteristic ultrasonographic abnormality (image 3 and image 4) [17,58,59]. In a meta-analysis of 14 studies, the pooled sensitivity of salivary gland ultrasonography to detect characteristic glandular abnormalities was 75 to 84 percent and pooled specificity was 88 to 95 percent, depending on the scoring system [60].
Sialograms obtained after instilling contrast into the salivary ducts may reveal sialectasis and pruning of the peripheral branches (picture 5). However, sialography is less commonly used today. Magnetic resonance imaging (MRI) may show diffuse enlargement of the glands with or without sialectasis (image 1 and image 5).
Lacrimal gland enlargement is a rare presenting feature of SS [61], being more commonly seen in IgG4-related disease, sarcoidosis, and lymphoma; its development in a patient with known SS should raise concern for the latter, particularly if there is asymmetric involvement.
Patients with SS are at increased risk for lymphoma, which is described briefly here (see 'Lymphoma' below) and in detail separately (see "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Lymphoma'). A number of other conditions may also cause unilateral or bilateral glandular enlargement, including infectious, obstructive, systemic, and other disorders (table 1).
Lymphoma — Lymphoma is one of the most serious complications of SS; it is estimated to occur in up to 5 to 10 percent of patients, consistent with a five- to ninefold increase in risk compared with an age-matched healthy population [62]. These tumors can arise in exocrine glands, lymph nodes, and from mucosa-associated lymphoid tissues. Lymphoma in SS is described in detail separately. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Lymphoma'.)
Briefly, findings associated with lymphoma may include:
●Persistent unilateral or bilateral glandular swelling, especially when previous swelling has been transient or intermittent
●Hard, nodular texture to the gland
●Presence of cryoglobulinemia, with cutaneous vasculitis or palpable purpura
●Hypocomplementemia
●Systemic features (malaise, weight loss, fever)
OTHER FEATURES — Other organs that may be affected by symptoms and sequelae of dryness, as well as other clinical manifestations, are described in detail separately. The dryness in these areas is explained only in part by exocrine deficiencies. Briefly, these include:
●Cutaneous manifestations – Excessively dry skin, xerosis, is the most common cutaneous manifestation of Sjögren's syndrome (SS) and often associated with pruritus. However, demonstration of an inflammatory process involving eccrine glands has been inconsistent [63]. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Skin' and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Xerosis'.)
●Respiratory tract manifestations – Upper and lower airway involvement may be associated with persistent dry cough, hoarseness, and nasal dryness and crusting. Inflammation of submucosal glands in the respiratory tract was originally demonstrated by Sjögren in his initial description of the syndrome [64]. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Lungs'.)
●Gynecologic manifestations – Vulvovaginal dryness, pruritus, and dyspareunia may occur, and urogenital involvement may be complicated by bacterial and candidal infections. However, the vagina has no secretory glands, and its basal humidification and lubrication during sexual arousal depends upon fluid transudation across the vaginal epithelium. Increased lymphocytic infiltration is found in vagina biopsies of women with SS compared with controls, and this might lead to vascular dysfunction [65]. Involvement in SS of the Bartholin and Skene glands at the vaginal vestibule, which have a minor role in lubrication of the vulva, has been suggested but never proven [52]. Gynecologic involvement in SS is described separately. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Urogenital disease'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Sjögren's syndrome (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Sjögren's syndrome (SS) is a chronic systemic autoimmune disorder characterized by diminished lacrimal and salivary gland function. SS occurs in primary and secondary forms. The major signs of exocrine gland involvement are dry eyes and dry mouth, caused by immune-mediated inflammation directed against the exocrine glands of the eyes and mouth. Histopathologic features include extensive focal lymphocytic infiltration, with glandular and ductal atrophy. (See 'Pathogenesis and histopathology' above and 'Epidemiology' above.)
●Dry eye, caused by a reduction in the aqueous component of tears, usually presents insidiously over a period of several years. Patients may complain of a "gritty" or "sandy" feeling in their eyes, especially at night, rather than "dryness." Physical examination may include punctate conjunctival and corneal damage and evidence of reduced tear production. (See 'Dry eye' above.)
●Dry mouth symptoms result from chronic salivary hypofunction. Patients may also complain of dysphagia, adherence of food to buccal surfaces, problems with dentures, changes in taste, or an inability to eat dry food or to speak continuously for long periods. Chronic complications include dental caries and oral candidiasis. (See 'Clinical features of dry mouth' above and 'Complications of salivary hypofunction' above and 'Oral candidiasis' above.)
●Salivary gland enlargement may be either chronic or episodic, and glands are usually firm, diffuse, and nontender. It most often affects the parotid glands, but the submandibular glands may be similarly involved. A particularly hard or nodular gland may suggest a neoplasm. Lacrimal gland enlargement can also occur in SS. (See 'Salivary and lacrimal gland enlargement' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.
