INTRODUCTION — Sjögren’s disease (SjD) is a chronic autoimmune inflammatory disorder characterized by diminished lacrimal and salivary gland function with resultant dryness of the eyes and mouth [1,2]. In addition, a variety of other disease manifestations affecting multiple organs and organ systems may occur, and the clinical features of SjD can be divided into the two broad categories of exocrine glandular features and extraglandular features . Disease severity can vary over a wide range. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease".)
SjD occurs in a primary form not associated with other diseases and in a secondary form that complicates or overlaps with other rheumatic conditions . The most common diseases associated with SjD are rheumatoid arthritis and systemic lupus erythematosus. SjD is most common in women in their 50s and 60s but can affect adolescents and young adults, as well as men.
This topic will review the epidemiology, diagnosis, differential diagnosis, and classification of SjD. The clinical manifestations, pathogenesis, treatment, and prognosis of this disorder are discussed separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Pathogenesis of Sjögren’s disease" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease" and "Overview of the management and prognosis of Sjögren's disease".)
NOMENCLATURE — Several different terms have been used to refer to patients with Sjögren’s disease (SjD) or clinically similar syndromes:
●Sjögren's disease is an alternative name for Sjögren's syndrome. Its use has been advocated by the author of this topic and the Sjögren's Foundation, in part due to concerns that "syndrome" implied to some a collection of nuisance symptoms rather than a distinct autoimmune disease with potentially serious outcomes .
●Sicca syndrome is a synonym for SjD, rarely used in current medical textbooks but used as a diagnostic term in the International Classification of Diseases (ICD) schema through September 2021. It should not be confused with "sicca complex," a term that refers to dryness of the eyes and mouth without specification as to underlying etiology.
●Keratoconjunctivitis sicca (KCS) is generally used to denote the ocular findings of SjD. The term was originated by the Swedish ophthalmologist Henrik Sjögren in his 1933 description of the syndrome .
●Dry eye syndrome (DES) and dysfunctional tear syndrome have been used to refer to conditions that cause ocular dryness, which may result from aqueous tear deficiency (eg, SjD) and from excessive evaporation (eg, meibomian gland dysfunction) (table 1) [7,8]. (See "Dry eye disease".)
●Mikulicz syndrome, which is characterized by prominent parotid and lacrimal glandular enlargement, may result from SjD as well as other conditions, including immunoglobulin G4 (IgG4)-related disease [9-11]. According to a 2005 review of Mikulicz's original paper, the index patient most likely had a mucosa-associated lymphoid tissue (MALT) lymphoma (subsequently renamed extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue) of the salivary and lacrimal glands . (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Lymphoma' and "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Salivary and lacrimal gland involvement'.)
DISEASE SPECTRUM — There is a broad range of disease severity, spanning mild glandular dryness and constitutional symptoms to severe glandular involvement and a variety of extraglandular manifestations and systemic autoimmune features. Challenges in establishing the diagnosis thus range from evaluating its presence in a patient with symptoms of ocular and/or oral dryness to differentiating the condition from other systemic autoimmune disorders (eg, systemic lupus erythematosus) or causes of salivary gland enlargement. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease".)
As examples, the spectrum of disease presentations includes:
●At the mild to moderate end of the spectrum are patients with dry eyes and dry mouth, often in association with fatigue, myalgia, and mild cognitive dysfunction. The diagnosis of Sjögren’s disease (SjD) in these patients is necessarily supported by a positive test for anti-Ro/SSA antibodies and/or a labial salivary gland biopsy showing focal lymphocytic sialadenitis with a focus score ≥1 (ie, "positive" lip biopsy). Such patients may be difficult to distinguish clinically from patients with fibromyalgia or depression who have ocular and/or oral dryness caused or exacerbated by medications with anticholinergic side effects.
●A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.
●A small group of patients have primarily extraglandular manifestations and positive testing for Ro/SSA antibodies without significantly dry eyes or dry mouth. The laboratory findings may be found during evaluation of neuropathies, nephropathies, interstitial pneumonitis, hematologic abnormalities, lymphoproliferative changes, or abnormalities of other organs with a pattern of extraglandular disease suggestive of either SjD or systemic lupus erythematosus.
Sjögren's syndrome — Estimates of the incidence and prevalence of Sjögren’s disease (SjD) vary widely, depending upon the specific classification criteria, study design, and the population examined. Only a small minority (approximately 10 percent) of patients with clinically significant dry eye have SjD. The following observations illustrate the range of findings:
●In a 2015 meta-analysis of population-based studies, the overall incidence of SjD was estimated at approximately 7 per 100,000 person-years . The highest incidence rates were reported in studies from Europe and Asia. The prevalence in the meta-analysis was estimated at 43 per 100,000 people (0.043 percent) . Reported prevalence rates in other population-based studies have varied from 0.01 to 0.09 percent, related in part to differences in case ascertainment [14-16].
●In a subsequent population-based study from Olmsted County, Minnesota that was not included in the above meta-analysis, the annual incidence of physician-diagnosed primary SjD was 5.8 per 100,000 person-years, based upon a review of medical records for the period of 1976 to 2015 . The prevalence was 10.3 per 10,000 inhabitants.
●SjD was identified, based upon the American-European Consensus Group (AECG) criteria, in 11.6 percent of 327 patients in a prospective cohort with clinically significant aqueous-deficient dry eye who were drawn from a variety of eye care practices, including 6.4 and 5.2 percent with primary and secondary SjD, respectively . (See 'Classification criteria' below.)
SjD has a worldwide distribution, and its phenotype may vary as a function of geolocation and ethnicity. In an analysis of 8310 subjects with primary SjD in an international, multicenter registry, the ratio of women to men was highest in Asian (27:1) and lowest in Black or African American (7:1) patients (where Asian was defined as "a person having origins in any of the original peoples of the Far East, Southeast Asia or the Indian subcontinent"; and Black or African American was defined as "a person having origins in any of the Black racial groups of Africa"); and sicca symptoms had the lowest prevalence in Asian patients . North-south gradients in certain findings were evident, with less frequent ocular involvement in northern Europe and Asia and higher frequencies of antinuclear antibodies (ANA) in northern American countries and northern Asia, but lower ANA frequencies in northern Europe .
Dry eye and mouth in older adults — Sicca symptoms are much more common than SjD, with a higher prevalence in older adults, approximately 30 percent of whom have symptoms of dry eyes and/or dry mouth [20-23]. Sicca symptoms in older adults are due partly to medications and partly to age-related atrophy of secreting tissue and resultant declines in tear and basal (unstimulated) whole saliva flow rates [24-26].
In an epidemiologic survey of 2341 adults aged 65 years or older and residing in Salisbury, Maryland, 15 percent had dry eye and 17 percent dry mouth symptoms [22,23,27]. Objective measures of ocular and oral dryness were found in only 4 percent of each of the groups with symptoms. Ocular and oral dryness symptoms were both present in 4.4 percent of the residents. Autoantibodies were present in 16 percent, including ANA ≥1:320 (11 percent), rheumatoid factor (6 percent), and anti-Ro/SSA and/or anti-La/SSB (1.4 percent). A diagnosis of SjD, defined by the presence of dry eyes and dry mouth and any autoantibody, was found in one resident (prevalence 0.04 percent) .
Diagnostic criteria — The diagnosis of Sjögren’s disease (SjD) can be made in individuals with an objective finding of ocular and/or oral dryness for whom there is substantive evidence of an underlying autoimmune basis for the exocrine glandular dysfunction. SjD should be suspected in individuals with persistent symptoms of dry eyes and/or mouth, parotid gland enlargement, an unexplained increase in dental caries, or abnormal results of specific serologic tests (eg, anti-Ro/SSA antibodies with or without anti-La/SSB antibodies, rheumatoid factor, and hyperglobulinemia). (See 'Symptoms of dry eyes and mouth' below.)
There is no single diagnostic test for SjD; thus, the clinical diagnosis of SjD is made in the presence of compatible clinical and laboratory features and after the exclusion of other causes of ocular and/or oral dryness (see 'Differential diagnosis' below). SjD should not be diagnosed based solely upon the presence of antibodies to SSA/Ro and/or SSB/La, as these antibodies can be found not only in patients with SjD, but in other rheumatic/connective diseases, as well as in healthy individuals.
We make a diagnosis of SjD if the following two criteria, as defined here, are met and other causes of ocular and/or oral dryness have been excluded (see 'Diagnostic evaluation' below):
●Objective findings of ocular or oral dryness or of glandular parenchymal damage – The patient has an objective marker of dry eye (Schirmer test in either eye of <5 mm/5 minute or abnormal ocular surface staining) (see 'Schirmer test' below and 'Ocular surface staining' below) or salivary hypofunction (abnormal Saxon test or whole sialometry). (See 'Quantifying salivary hypofunction' below.)
Alternatively, the patient may have computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound (US) evidence of significant glandular parenchymal abnormalities characteristic of SjD . (See 'Magnetic resonance imaging' below and 'Salivary gland ultrasonography' below.)
●Evidence of underlying autoimmunity – The patient has anti-Ro/SSA antibodies with or without anti-La/SSB antibodies (see 'Antibodies to Ro/SSA and La/SSB' below), a positive labial salivary gland biopsy (ie, focal lymphocytic sialadenitis with focus score ≥1) (see 'Salivary gland biopsy' below), or a well-established systemic rheumatic disease (eg, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis [scleroderma], or idiopathic inflammatory myopathy). (See 'Diagnostic testing' below.)
Alternatively, the patient may have anticentromere antibodies (in the absence of systemic sclerosis) or the combination of an antinuclear antibody (ANA) ≥1:320 with a positive rheumatoid factor [29,30].
The term "secondary SjD" is traditionally applied to those patients in whom the lacrimal and salivary gland dysfunction is present in the setting of a well-established systemic rheumatic disease.
We are cautious in accepting weakly positive tests for anti-Ro/SSA or anti-La/SSB as supportive of a diagnosis of SjD. With the typical multiplex solid-phase immunoassays in widespread use, this would represent results just above the upper limits of normal and/or those which are not consistently positive when tested by different assay systems. This is particularly true when anti-La/SSB antibodies are the only finding . In these cases, we obtain a labial salivary gland biopsy to confirm a diagnosis of SjD.
Our definition facilitates the diagnosis of SjD in children, in whom recurrent parotitis is common, but objective markers of oral or ocular sicca may be absent.
Individuals presenting with a systemic manifestation, such as interstitial pneumonitis or interstitial nephritis, may lack ocular and oral sicca but still be diagnosed with SjD if they have a positive labial salivary gland biopsy and anti-Ro/SSA antibodies.
Diagnostic evaluation — Patients suspected of SjD should undergo a thorough medical history and physical examination (see 'Symptoms of dry eyes and mouth' below and 'Physical examination' below) with attention to characteristic features of SjD, other systemic rheumatologic autoimmune diseases (eg, systemic lupus erythematosus and rheumatoid arthritis), and conditions that may resemble SjD. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and 'Differential diagnosis' below.)
Diagnostic testing, including ophthalmologic consultation for an ocular examination, selected blood tests, and other testing, are also important elements of the evaluation (see 'Diagnostic testing' below). Many patients do not require diagnostic testing beyond the initial blood tests and examination by an expert in eye disease, although some patients may require formal testing of salivary function, a labial salivary gland biopsy, and/or imaging studies. An oral medicine specialist can facilitate a more comprehensive diagnostic evaluation through assessment of salivary hypofunction and performance of the labial salivary gland biopsy.
Symptoms of dry eyes and mouth — The diagnosis of SjD should be suspected when symptoms of ocular and oral dryness have persisted on a daily basis for three or more months. A history of these symptoms may be elicited from the patient by the use of specific validated questions [24,32]:
●Ocular symptoms – The symptoms of dry eyes may be sought with questions such as:
•"Have you had daily, persistent, troublesome dry eyes for more than three months?"
•"Do you have a recurrent sensation of sand or gravel in the eyes?"
•"Do you use tear substitutes more than three times a day?"
●Oral symptoms – Symptoms of mouth dryness (ie, xerostomia) and sialadenitis may be elicited by questions such as:
•"Have you had a daily feeling of dry mouth for more than three months?"
•"Do you have to wake up at night to drink water because your mouth is so dry?" 
•"Do you frequently drink liquids to aid in swallowing dry food?"
•"Have you had recurrently or persistently swollen salivary glands as an adult?"
Physical examination — Patients should undergo a thorough physical examination, with particular attention to the presence of salivary gland enlargement and signs of salivary hypofunction, including caries at the cervical and incisal portions of the teeth, a hyperlobulated tongue with loss of filiform papillae, and absence of salivary pooling under the tongue. An online pictorial atlas may facilitate the assessment and scoring of oral dryness signs . Clinically overt lacrimal gland enlargement is unusual in SjD, and its finding should prompt concern for alternative diagnoses (eg, immunoglobulin G4 [IgG4]-related disease, sarcoidosis, lymphoma) or intervening lymphoma in a patient with known SjD. (See 'Differential diagnosis' below.)
Sublingual salivary pooling can be assessed as follows: Dry the sublingual space with a gauze pad and then observe over one minute for the pooling of saliva. Copious pooling of saliva is a strong argument against salivary hypofunction, even if the patient reports dry mouth symptoms. Similarly, the absence of any pooling is abnormal.
Other potential signs include palpable purpura of the lower legs, peripheral neuropathy, and chronic erythematous candidiasis of the oral cavity. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Oral candidiasis'.)
Diagnostic testing — In addition to a thorough medical history and physical examination, the following diagnostic steps are recommended when SjD is suspected:
●Laboratory testing – Basic laboratory tests should be obtained or reviewed to define the presence of abnormalities that can be seen in SjD. These abnormalities include leukopenia, thrombocytopenia, and anemia (complete blood count with differential); hyperglobulinemia (erythrocyte sedimentation rate [ESR], total globulins, immunoglobulin quantitation); proteinuria and/or hematuria reflective of the rare occurrence of glomerulonephritis (urinalysis); and findings indicative of possible renal tubular acidosis secondary to interstitial nephritis, including mild proteinuria, hyposthenuria, and urine pH ≥7 in the face of a metabolic acidosis (basic metabolic panel, urinalysis, and spot urine protein-to-creatinine ratio).
●Ophthalmologic evaluation – All patients should be evaluated by an eye professional, such as an ophthalmologist, for the presence of dry eye on a formal eye examination.
The examination should include Schirmer testing (see 'Schirmer test' below), a slit-lamp examination for assessment of tear break-up time (TBUT) (see 'Tear break-up time' below), and ocular surface staining (see 'Ocular surface staining' below). Although the Schirmer test can be done by any practitioner, the eye professional can perform and interpret the more specialized tests needed and also evaluate for and treat alternative causes of dry eye or ocular irritation, such as meibomian gland dysfunction or allergic conjunctivitis. (See 'Differential diagnosis' below.)
●Evaluation for salivary hypofunction – In patients whose tests for dry eye do not support the diagnosis of SjD or when salivary gland symptoms predominate, an evaluation for salivary hypofunction, characteristic salivary gland parenchymal change on imaging, or focal lymphocytic sialadenitis by labial salivary gland biopsy should be performed (see 'Salivary gland biopsy' below):
•Salivary gland imaging – Either US or MRI can be used to define characteristic changes in the salivary gland parenchyma that would support a diagnosis of SjD (see 'Magnetic resonance imaging' below and 'Salivary gland ultrasonography' below). Of the two, the author prefers the less expensive salivary gland US. In a meta-analysis of 14 studies, salivary gland US had a pooled sensitivity of 75 percent and specificity of 93 percent for SjD . Punctate calcification of both parotid glands on CT imaging (image 1) has high specificity but low sensitivity for the SjD diagnosis . Due to concerns regarding irradiation and low sensitivity, CT imaging is not recommended as part of the routine SjD diagnostic evaluation. Parotid scintigraphy and contrast sialography also define characteristic abnormalities in SjD but are used infrequently. (See 'Other imaging techniques' below.)
•Sialometry – Results of sialometry indicative of salivary hypofunction can support the diagnosis of SjD, although such testing may not be available in many practices and is primarily performed in research settings. (See 'Quantifying salivary hypofunction' below.)
The whole sialometry and Saxon tests are not difficult to perform but require an analytical balance, a piece of equipment that is often not available in the routine clinical setting. Such tests should not be performed while the patient is taking drugs with anticholinergic side effects as this will influence the results of the testing.
●Evidence of systemic autoimmunity – All patients should be evaluated for evidence of underlying systemic autoimmunity:
•Serologic testing – Patients should be tested for anti-Ro/SSA and anti-La/SSB antibodies, ANA by an immunofluorescence assay, and rheumatoid factor (see 'Antibodies to Ro/SSA and La/SSB' below and 'Other autoantibodies in SjD' below). Support for the diagnosis of SjD would include positive testing for anti-Ro/SSA antibodies with or without anti-La/SSB antibodies, the combination of an ANA ≥1:320 with a positive rheumatoid factor, or the presence of a centromere staining pattern on the immunofluorescent ANA test . Rheumatoid factor is present in 40 to 60 percent of patients. The ANA should not be used as a screening test for SjD or for SS-related antibodies, since some patients may have anti-Ro/SSA and/or anti-La/SSB antibodies despite a negative immunofluorescence assay for ANA.
•Systemic rheumatic disease – In patients with symptoms or signs of systemic rheumatic disease, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, or idiopathic inflammatory myopathy, additional testing should be performed to confirm their presence. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Diagnostic approach'.)
●Testing to exclude SjD mimics – Certain systemic diseases with clinical manifestations that can mimic SjD should be excluded with selected laboratory testing:
•In patients with risk factors for selected infectious conditions, including hepatitis C, human immunodeficiency virus (HIV), and human T-cell lymphotropic virus (HTLV) type I, appropriate diagnostic testing should be obtained. (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Screening and diagnostic testing for HIV infection" and "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)
•In patients with salivary or lacrimal gland enlargement, a serum IgG4 level should be obtained. Enlargement of both submandibular glands without enlargement of the parotid glands is common in IgG4-related disease but unusual in SjD [37,38] (see "Diagnosis and differential diagnosis of IgG4-related disease"). Similarly, clinically overt lacrimal gland enlargement is unusual in SjD unless there is a supervening lymphoma.
•In patients with clinical findings suggesting possible sarcoidosis, a plain radiograph of the chest should be obtained. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Extrapulmonary manifestations of sarcoidosis".)
●Labial salivary gland biopsy – Labial salivary gland biopsy ("lip biopsy") remains an important diagnostic test:
•In patients who lack evidence for systemic autoimmunity, such as the relevant autoantibodies or concomitant autoimmune diseases (see 'Diagnostic criteria' above), labial salivary gland biopsy is essential to confirm the diagnosis. It should also be performed for this purpose when the sole evidence for systemic autoimmunity is the finding of weakly positive anti-Ro/SSA test results or the presence of anti-La/SSB antibodies in the absence of anti-Ro/SSA antibodies. Confirmation of a diagnosis of SjD with a lip biopsy has particular utility if the results would influence the choice of therapies for nonsicca manifestations, such as fatigue, arthritis, or peripheral neuropathy.
•It may define the presence of alternative diagnoses, such as sarcoidosis, IgG4-related disease (IgG4-RD), and amyloidosis, which can mimic SjD. (See 'Differential diagnosis' below.)
•It informs disease prognosis. Greater degrees of lymphoid infiltration (eg, higher focus score) are associated with an increased risk for the later development of lymphoma . The same was true for the presence of germinal center-like structures in the minor salivary glands in one study, but not confirmed in another [40,41]. The labial gland biopsy may rarely reveal lymphoma in patients with SjD .
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Sjögren’s disease (SjD) includes diseases that cause sicca symptoms and/or salivary or lacrimal gland enlargement (table 1). Most of these conditions can be excluded based upon the history and physical examination, along with a lack of evidence for systemic autoimmunity. The following entities may mimic SjD because of their potential involvement of both the lacrimal and salivary glands:
●Age-related sicca syndrome – Age-related ocular and oral dryness may mimic those features of the typically younger patient who develops SjD; evidence of systemic disease, the usual immune-mediated histologic changes seen in SjD, and SjD-related antibodies (anti-Ro/SSA and anti-La/SSB) are usually absent in patients with age-related dryness. Tear and unstimulated saliva production decline with age [25,26], most likely as a result of age-related histologic alterations in lacrimal and salivary glands, including acinar atrophy, interstitial fibrosis, and ductal dilatation . Although the onset of SjD is rare after age 65 , care must be taken in the evaluation of older adult patients with sicca symptoms, since positive tests for antinuclear antibodies (ANA) and rheumatoid factor increase in prevalence with age . (See "Dry eye disease".)
●IgG4-related disease – IgG4 plasmacytic infiltration underlies several related forms of lacrimal and salivary gland disease, including orbital inflammatory pseudotumor, chronic sclerosing sialadenitis (Küttner tumor), and "Mikulicz disease" . These IgG4-related diseases (IgG4-RD) can be distinguished from SjD by their associated clinical and laboratory features and the distinct histopathologic findings seen in IgG4-RD. Enlargement or induration of the glands, sometimes with severe dysfunction, is characteristic. Patients with these forms of IgG4-related plasmacytic salivary and lacrimal gland disease may have systemic disease (IgG4-RD), manifested by contemporaneous or past involvement of other organs with a common pathologic process marked by IgG4 plasmacytic infiltration, extensive fibrosis, and obliterative phlebitis. The most common is sclerosing pancreatitis; others include lymphoplasmacytic aortitis, retroperitoneal fibrosis, sclerosing cholangitis, and inflammatory pseudotumors of the lung, breast, or liver. Elevated serum IgG4 levels and eosinophilia are often present. (See "Pathogenesis and clinical manifestations of IgG4-related disease" and "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Salivary and lacrimal gland involvement'.)
●Eosinophilic sialodochitis (sialodochitis fibrinosa or Kussmaul disease) – Recurrent and paroxysmal swelling of the submandibular and/or parotid glands may arise from eosinophilic inflammation of their larger ducts [47,48]. The presence of mucus plugs laden with eosinophils is a characteristic feature. The majority of patients have background atopic illness (eg, asthma, rhinitis, eczema) with peripheral eosinophilia and elevated IgE levels. The diagnosis rests on the detection of eosinophils in saliva specifically collected from cannulation of Wharton or Stensen duct or in flocculant saliva material or plugs expressed from the glands with massage. Imaging shows dilatation of the intraglandular ducts. Core needle biopsies or resected glands show intense periductal eosinophilic inflammation with ductal epithelial hyperplasia. (See "Salivary gland swelling: Evaluation and diagnostic approach", section on 'Immune-mediated sialadenitis'.)
●Benign lymphoepithelial sialadenitis and dacryoadenitis – This is a distinct pathologic entity in which the lacrimal and/or major salivary glands show extensive lymphocytic infiltration with acinar atrophy and the formation of numerous "lymphoepithelial lesions." The latter are islands of epithelial cells within the lymphoid infiltrate that arise from lymphocytic invasion of the ductal epithelium, followed by proliferation of the basal epithelial cells and disorganization of the ductal structure. It is in fact the characteristic histopathology of the lacrimal and salivary glands in advanced SjD, originally described by Sjögren in 1933  and highlighted in a classic study by Morgan and Castleman in 1953 . However, this pathologic entity may not be restricted to patients with SjD, occurring in an "idiopathic" form in up to 50 percent of cases reported in pathologic series [50-52]. It is a precursor of mucosa-associated lymphoid tissue (MALT) lymphoma (subsequently renamed extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue) of the salivary gland  and is difficult to differentiate from lymphoma . Patients who have this pathologic lesion defined during the course of an evaluation for salivary gland enlargement should be evaluated for SjD and other autoimmune diseases. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging" and "Pathology of head and neck neoplasms", section on 'Salivary gland tumors'.)
●Lymphoma and other hematologic malignancy – Malignant infiltration of the parotid glands may occur in both childhood and adult forms of leukemia and typically presents with bilateral salivary and lacrimal gland enlargement. Primary lymphomas of the parotid glands usually present as unilateral tumors, but bilateral involvement was observed in 2.3 percent of 2140 affected patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database . (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)
Lymphomatous transformation of benign lymphoepithelial sialadenitis in SjD can manifest as a solitary nodule, sometimes arising in a gland that has been chronically enlarged, or progressive bilateral enlargement. Lacrimal gland enlargement in SjD should raise concern for supervening lymphoma.
●Sarcoidosis – Occasionally some features of sarcoidosis may resemble SjD, including parotid (4 to 6 percent of patients with sarcoidosis) and lacrimal (7 to 16 percent of patients with sarcoidosis) gland enlargement [56-59]. SjD and sarcoidosis also share extraglandular manifestations, including arthritis and interstitial nephritis . Sarcoidosis may rarely present as Heerfordt's syndrome with acute bilateral enlargement of the parotid, submandibular, and lacrimal glands, and occasionally with fever. Sarcoidosis and SjD can be distinguished on biopsy if the distinction cannot be readily made based upon the clinical findings. (See "Extrapulmonary manifestations of sarcoidosis".)
●Hepatitis C – SjD may rarely arise in the context of chronic hepatitis C virus (HCV) infection. Despite clinical and immunologic similarities , some histologic features may differ and symptoms of dryness may be less frequent . SjD patients with HCV differ from noninfected SjD patients, having an older age at diagnosis; a higher prevalence of males, hepatic involvement, cryoglobulinemia, cutaneous vasculitis, peripheral neuropathy, rheumatoid factor, and hypocomplementemia; and a lower prevalence of anti-Ro/SSA and anti-La/SSB antibodies . HCV infection should be sought in SjD patients, particularly those with hepatitis and cryoglobulinemia, since treatment approaches will differ. (See "Screening and diagnosis of chronic hepatitis C virus infection".)
●HIV infection – Diffuse CD8 lymphocytosis syndrome is a manifestation of HIV infection that may mimic SjD, the incidence of which has declined sharply with the advent of highly active antiretroviral treatment [63,64]. Affected patients develop parotid gland enlargement, sicca symptoms, and lymphocytic interstitial pneumonitis. Salivary gland biopsies show a CD8-predominant lymphocytic infiltrate . In the United States, the syndrome occurs more commonly in African Americans than in White Americans or Mexican Americans.
●Graft-versus-host disease – Dry eye and dry mouth symptoms are reported by the majority of patients with chronic graft-versus-host disease developing after allogeneic hematopoietic stem cell transplantation. In one study from the National Institutes of Health, lacrimal gland dysfunction was documented in 82 percent and salivary gland hypofunction in 27 percent of patients . Minor salivary gland biopsies showed prominent acinar atrophy and interstitial fibrosis. Periductal inflammation was seen, but the extent of lymphocytic infiltration was less than in SjD, and patients can generally be distinguished from those with SjD based upon the clinical context. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)
●Sicca induced by immune checkpoint inhibitor therapy – Oral and/or ocular dryness can occur relatively abruptly in the context of therapy with immune checkpoint inhibitors for neoplastic disease [67,68]. In most patients, oral dryness is the dominant clinical feature. This syndrome most often arises de novo, in the absence of a recognized pre-existing autoimmune disease, and lacks systemic manifestations. In a minority, there may be concomitant systemic manifestations, such as arthritis, rash, and interstitial pneumonitis . (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'Sicca syndrome/other ocular disorders'.)
●Systemic vasculitis – Bilateral parotid and submandibular gland enlargement is a rare manifestation of granulomatosis with polyangiitis (GPA) . Clinical, laboratory, and histologic differences distinguish these manifestations of GPA from SjD. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
Tests for dry eye — There are three commonly used tests for dry eye: the Schirmer test, ocular surface staining, and tear break-up time (TBUT). The last two tests require a slit lamp examination by an eye care professional. We routinely request a formal ophthalmologic evaluation for the assessment of patients with possible or known Sjögren’s disease (SjD), since it may also serve to detect meibomian gland dysfunction and other factors that may be contributing to the presence of dry eye.
Schirmer test — Reflex tear production is measured using the Schirmer test. A folded test strip of sterile filter paper, supplied in a standard kit, is placed over the margin of each lower eyelid at the junction of the middle and lateral thirds. The extent of wetting is measured over five minutes with the patient's eyes gently closed . The test is performed without topical anesthesia to assess reflex tearing, although topical anesthesia can be used to assess basal tear production. Wetting of less than 5 mm without anesthesia is indicative of aqueous tear deficiency and is a classification criterion for SjD [72,73]. The findings are typically similar in both eyes.
Ocular surface staining — Damage to conjunctival and corneal epithelial cells may be assessed with vital dyes that stain areas of devitalized tissue (picture 1 and figure 1A-B). Rose Bengal dye stains devitalized tissue in both the cornea and the conjunctiva. Since the use of Rose Bengal dye is painful in patients with dry eyes, it is being supplanted by that of fluorescein (to stain the cornea) and lissamine green (to stain the conjunctiva).
To use the Rose Bengal dye, 10 microliters of 1 percent Rose Bengal are instilled into the inferior fornix of the anesthetized eye. The patient is asked to blink twice to spread the dye over the conjunctiva and cornea. To use the fluorescein and lissamine green dyes, sequential examinations are required [74,75]. First, fluorescein is instilled, and both TBUT (see 'Tear break-up time' below) and corneal staining are assessed with a slit lamp (with a cobalt blue filter) in a period of less than four minutes. Second, a drop of 1 percent lissamine green dye is instilled in each unanesthetized eye. Excess dye is wiped away and the eyes are then observed immediately with a slit lamp. The dyes typically stain the exposed ocular surface between the palpebral fissures.
The degree of ocular surface staining is scored with one of several published schema; the van Bijsterveld scoring may be used for Rose Bengal staining  and the Sjögren's International Collaborative Clinical Alliance (SICCA) scoring method for fluorescein/lissamine green staining . A diagnosis of SjD is supported by staining scores of ≥4 by the van Bijsterveld method and ≥5 by the SICCA method (figure 1B). Other scoring schema, such as the Oxford, have not been validated with patient data for the diagnosis of SjD .
Fluorescein staining of the cornea is commonly performed by general ophthalmologists as part of a dry eye evaluation, while the opposite is true for staining of the conjunctiva with lissamine green or Rose Bengal . Nonetheless, the presence of conjunctival staining has particular value in predicting the presence of SjD . In addition, determination of ocular surface staining scores with conjunctival and fluorescein staining is a key component of classification criteria for the disease (see 'Classification criteria' below) and provides a measure of severity for stratification of patients and monitoring of treatment response .
Tear break-up time — The TBUT measures tear stability. It is performed by staining the tear film with one drop of fluorescein dye and measuring the time in seconds for a dry spot, or disruption in the tear film, to develop. Visualization of the tear film with slit-lamp magnification and cobalt blue light is required. A TBUT of ≤10 seconds is abnormal and indicative of a deficiency or abnormal quality of the outermost lipid layer of the tear film, derived primarily from the oily secretions of the meibomian glands. The test may thus be abnormal in patients with normal tear production, such as those with disorders of the meibomian glands . Similarly, meibomian gland dysfunction is a frequent component of the dry eye disease of patients with SjD and requires specific treatment . (See "Blepharitis" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy".)
Quantifying salivary hypofunction — Several tests may be employed to quantify salivary hypofunction; these tests are primarily performed in research settings:
●Salivary gland scintigraphy – Quantitative salivary gland scintigraphy, also termed technetium excretion radionuclide scanning, provides a dynamic picture of the function of all major salivary glands . The finding of very low uptake of the radionuclide is relatively insensitive but highly specific for SjD. Approximately one-third of patients with SjD have positive tests .
●Whole sialometry – Sialometry is the measurement of the rate of saliva production. Protocols for the various methods have been published . The unstimulated whole salivary flow rate is a relatively simple test that assesses basal saliva production, primarily from the sublingual and submandibular glands, and avoids the need for special equipment or imaging agents. It declines with age and has a negative correlation with the extent of dental caries . The patient is asked to expectorate or swallow whatever saliva is in the mouth. The patient is then instructed to refrain from further swallowing and to collect all saliva into a preweighed container, either via continuous drooling or spitting once every minute. After 5 to 15 minutes, the collection vial is reweighed and the volume of saliva is calculated using the specific gravity for water (1 gram/mL). A collection of ≤0.1 mL/minute during this time is indicative of abnormal salivary function.
Whole sialometry can also be done with stimulation of saliva secretion, achieved with chewing or sialogogues (such as citric acid or pilocarpine). Such tests predominantly measure stimulated parotid saliva production.
Saliva quantitation using a pre-weighed sponge (also termed the Saxon test) is one method of whole stimulated sialometry. The patient chews a pre-weighed gauze sponge for two minutes without swallowing. The difference in the weight of the sponge before and after chewing represents the amount of saliva produced . Data from healthy individuals suggest that an accumulation of less than 2.75 grams of saliva on the sponge over a two-minute period constitutes a positive test . Disadvantages of the Saxon test include inadvertent swallowing of some saliva, the variability of saliva secretion with the time of day and with meals, and failure of the test to measure unstimulated salivary flow.
Salivary gland imaging — Several types of imaging can be used to define structural abnormalities of the salivary glands that can be seen in SjD. The two used most often are ultrasonography (see 'Salivary gland ultrasonography' below) and MRI (see 'Magnetic resonance imaging' below). Other techniques less often employed are CT and parotid gland contrast sialography. (See 'Other imaging techniques' below.)
Salivary gland ultrasonography — Salivary gland ultrasound (US) reveals characteristic abnormalities in the echo structure of the glandular parenchyma that can be graded and used for SjD diagnosis. The diseased gland in SjD typically shows multiple hypoechoic areas with convex borders (image 2) . Hyperechoic linear bands, cysts, and calcifications may be evident in more advanced disease.
Inclusion of salivary gland ultrasonographic results can improve the diagnostic performance of SjD classification criteria . In a study of 103 consecutive outpatients with clinically suspected SjD, salivary gland US, when compared with the 2016 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) classification criteria, had absolute agreement of 80 percent, sensitivity of 67 percent, and specificity of 94 percent . In a study of 72 patients with sicca syndrome, salivary gland ultrasound improved the sensitivity of the 2016 ACR/EULAR criteria to detect a clinical diagnosis of SjD (91.5 versus 89.4 percent) with a small decrease in specificity (96 versus 100 percent) .
Salivary gland ultrasonography can also replace ocular surface staining, Schirmer test, or sialometry in the ACR/EULAR classification criteria without any loss in their sensitivity or specificity . Abnormal salivary gland ultrasonography, defined primarily by the presence of hypoechoic foci in the glandular parenchyma, correlates strongly with the presence of anti-Ro/SSA antibodies . Thus, it cannot serve as a substitute for the labial salivary gland biopsy in a patient lacking these antibodies.
US-guided fine-needle aspiration and core needle biopsy of the major salivary glands is an important tool for assessment of solitary masses and asymmetric parotid gland enlargement, as these findings are concerning for the presence of a salivary gland lymphoma or other neoplasm [89,90].
Magnetic resonance imaging — MRI of the parotid glands in SjD (image 3) is characterized by inhomogeneity of the parenchyma on both T1- and T2-weighted sequences. There is typically a nodular pattern, characterized by multiple hypo- and hyperintense areas of varying size . This "honeycomb" or "salt-and-pepper" pattern is thought to arise from fatty infiltration, fibrosis, ductal dilatation, and lymphoid infiltration of parotid lobules. MRI results correlate well with those of salivary gland biopsy .
MRI also provides a noninvasive technique for performing sialography on salivary glands, although it may only be available in specialized centers [93-96]. Gadolinium-enhanced MR studies with heavily T2-weighted sequences and with digital subtraction methods for the suppression of fat signal can be used to visualize dilatation and/or stenosis of Stensen duct and thus have particular utility in the evaluation of patients with recurrent parotitis [93,94,97].
Because MRI is noninvasive, the only contraindications are those applicable to the performance of MR studies in general. In particular, gadolinium administration in the setting of significantly reduced renal function has been associated with the development of nephrogenic systemic fibrosis. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)
Other imaging techniques
●Computed tomography – CT of the parotid glands may reveal heterogeneity of the parenchyma, nodularity, abnormal fat accumulation, alterations in glandular size, and cysts . Diffuse punctate calcification, best seen on CT, is a highly specific finding for SjD (image 1) . CT involves ionizing radiation and is thus used less often than MRI and US.
●Parotid gland contrast sialography – Parotid gland sialography is performed by retrograde cannulation of the major salivary gland ducts, followed by instillation of a non-lipid-soluble contrast medium to avoid extravasation of lipid-soluble agents. Although this method gives excellent visualization of the ducts, it is limited by the risk of rupturing the duct and should not be performed during an episode of acute parotitis [98,99]. Sialography can be coupled with panoramic radiography and cone-beam or conventional CT to enable better visualization of the ductal system. This test has been largely supplanted by noninvasive MR sialography in the United States [93-96].
Serologic and other laboratory testing — Routine laboratory testing (complete blood count, chemistry panel, urinalysis, and erythrocyte sedimentation rate [ESR]) may reveal findings supportive of SjD, including leukopenia, elevated globulins, and elevated ESR (usually a reflection of the elevated globulins). The urine may reveal signs of glomerulonephritis (red cell casts, proteinuria) or tubulointerstitial nephritis/renal tubular acidosis (mild proteinuria, hyposthenuria, urine pH ≥7 in the face of a metabolic acidosis). Measurement of the random spot urine protein-to-creatinine ratio assures detection of the low molecular weight proteinuria characteristic of tubulointerstitial nephritis in SjD.
We recommend testing for antinuclear antibodies (ANA) by immunofluorescence staining assay, anti-Ro/SSA and anti-La/SSB antibodies, and rheumatoid factor. The ANA test should not be used as a screening test for SjD since some patients may have anti-Ro/SSA and/or anti-La/SSB antibodies despite a negative immunofluorescence staining assay for ANA.
Antibodies to Ro/SSA and La/SSB — Patients with primary SjD often possess antibodies to the Ro/SSA or La/SSB antigens, and many patients possess both. The frequency of anti-Ro/SSA and/or anti-La/SSB antibodies has varied between studies, but generally 60 to 80 percent of patients with primary SjD exhibit one or both of these autoantibodies. By contrast, in healthy persons in the United States and in China, the prevalence of anti-Ro/SSA antibodies is 0.5 to 1 percent [100,101]. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Sjögren's disease'.)
High-throughput solid phase immunoassays for anti-Ro/SSA and anti-La/SSB antibodies have a higher sensitivity but lower specificity than older assay methods; thus, care should be exercised in interpreting weakly positive test results with these immunoassays. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Detection of anti-Ro and anti-La antibodies'.)
Anti-Ro/SSA antibody reactivity is directed at two distinct polypeptide antigens with molecular weights of 60 kD and 52 kD that are encoded by different genes [102,103]. SjD patients may express activity against both the 60 kD and the 52 kD proteins or against either protein alone [104-106]. The majority show reactivity against both antigens . The presence of both anti-Ro60 and anti-Ro52 antibodies has been associated with more severe disease [106,108].
In considering the diagnosis of SjD, it is important to recognize that one of the subsets of systemic lupus erythematosus is characterized by antibodies to Ro/SSA, and the labeling of the antibody as "Sjögren's syndrome associated" (SSA) in the laboratory report may lead to confusion by suggesting that this antibody is specific for SjD, which it is not, as it is also found in patients with systemic lupus erythematosus and other conditions . (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Clinical significance'.)
Other autoantibodies in SjD — The presence of anticentromere antibodies defines a small subset (approximately 5 percent) of SjD patients who may have some features of systemic sclerosis (scleroderma), such as Raynaud phenomenon, but lack sufficient findings to make that diagnosis . Approximately one-half of the SjD patients with anticentromere antibodies lack antibodies to Ro/SSA and La/SSB, and the presence of anticentromere antibodies can help the diagnosis of SjD.
The presence of anticitrullinated peptide/protein antibodies (ACPA) does not alone indicate that patients have rheumatoid arthritis rather than SjD. ACPA are infrequently present in SjD patients who lack other features of rheumatoid arthritis, although these patients tend to have more articular involvement.
A panel of antibody tests for use in the diagnosis of early SjD is being marketed that includes tests for antibodies to murine parotid tissue proteins, including parotid secretory protein, carbonic anhydrase 6, and salivary protein-1. These novel antibodies have not been validated as markers of early SjD and have poor diagnostic performance in established SjD, both in adult and pediatric forms of the disease [111-113]. A human homologue of salivary protein-1 has not been identified. In addition, antibodies to parotid secretory protein, carbonic anhydrase 6, and other homologous human salivary gland proteins were not detected in SjD patients when sought by an independent laboratory . Further research is required to determine the utility of such testing in routine clinical practice.
Salivary gland biopsy — A labial salivary gland biopsy can serve as an important diagnostic tool in patients with suspected SjD. Indications for salivary gland biopsy in clinical practice include :
●Confirmation of a suspected diagnosis of SjD, particularly in patients without other evidence of autoimmunity
●Exclusion of other conditions that can cause salivary hypofunction and bilateral gland enlargement (see 'Differential diagnosis' above)
A labial salivary gland biopsy should be taken from a nontraumatized part of the lower lip that is macroscopically normal. Persistent lip numbness has been reported in up to 6 percent of patients who undergo the biopsy . The risk of this complication can be minimized with the use of a minimally invasive technique in which the initial incision of the labial mucosa only involves the epithelium and the individual glands are released from the surrounding fascia with blunt dissection, grasped and lifted slightly with Adson forceps prior to excision from the surgical field with iris scissors [117,118]. Care must be taken throughout the procedure to avoid damage to sensory nerve fibers that lie just below the minor salivary glands.
The biopsy should contain at least four lobules of salivary gland tissue to be considered acceptable for evaluation . The key histologic feature is a focal collection or collections of tightly aggregated lymphocytes, termed lymphocytic foci, which are typically periductal (image 4). This histologic pattern is known as focal lymphocytic sialadenitis. Certain pathologic features such as parenchymal atrophy, fibrosis, and scattered lymphoid cells are almost universal in older adults [43,120]. Biopsies with only these changes are classified as nonspecific chronic sialadenitis or sclerosing chronic sialadenitis, depending on severity. Biopsies showing focal lymphocytic sialadenitis may also show some or all of these pathologic features, and it is thought that these relate to the independent effects of aging rather than immune-mediated inflammation, but the consequences of chronic inflammation cannot be excluded. However, plasma cells and scattered T lymphocytes are normal findings in healthy glands belonging to the mucosal immune system.
The most widely accepted grading system for focal lymphocytic sialadenitis records the number of foci of lymphoid tissue in the tissue section, normalized to a surface area of 4 mm2 (focus score). Each focus is defined as a collection of 50 or more mononuclear lymphoid cells (predominantly lymphocytes with only a minority of plasma cells) that is adjacent to normal-appearing mucous acini and not in an area of glandular fibrosis or ductal dilatation [121,122]. Classification schema include focal lymphocytic sialadenitis in a minor salivary gland biopsy with one or more foci of lymphocytes per 4 mm2 (focus score ≥1) as the histopathologic criterion [29,123,124] (see 'Classification criteria' below). Analyses of large cohorts of individuals with suspected or established SjD have shown a significant association of this histopathologic lesion and focus score threshold with the phenotypic features of SjD [122,125].
Experience in the reading of labial salivary gland biopsies is critical for proper interpretation , and guidelines for this interpretive process are being established . Determination of the focus score in a labial salivary gland biopsy showing focal lymphocytic sialadenitis requires three steps. First, the surface area of the glandular tissue is measured in a single tissue section containing multiple glands sectioned through their midportion. This requires a calibrated reticule or computer-assisted image analysis. Second, the number of lymphocytic foci in the entire tissue section is counted. Care is taken to only count foci with 50 or more tightly aggregated lymphocytes that are adjacent to normal-appearing mucous acini. Third, the number of foci is divided by the total glandular surface area of the section and then multiplied by 4 to yield the focus score (number of foci/4 mm2). (See "Pathogenesis of Sjögren’s disease".)
A positive lip biopsy (showing focal lymphocytic sialadenitis with a focus score ≥1) is found in 66 to 89 percent of patients with SjD classified by the 2002 American-European Consensus Group (AECG) criteria, resulting in an approximate sensitivity of 80 percent [72,128,129]. However, it is not pathognomonic for SjD, being found in patients with other connective tissue disorders (rheumatoid arthritis, mixed connective tissue disease, systemic lupus erythematosus, limited systemic sclerosis) who lack sicca symptoms or signs  and in up to 15 percent of healthy older adults .
Immunocytology of labial salivary gland infiltrates shows that CD4+ T cells predominate in less severe lesions while B cells predominate in more advanced lesions . Germinal center-like structures are seen in approximately 20 percent of patients with focal lymphocytic sialadenitis and may identify a particular phenotype of SjD with a higher prevalence of autoantibodies . The presence of germinal center-like structures has been shown to be a predictor for the development of malignant lymphoma in some studies [40,41]. Defining the presence or absence of these germinal center-like structures has been cited as an additional indication for labial salivary gland biopsy . Immunocytology is a requisite tool for defining the presence of alternative diagnoses, such as IgG4-related disease (IgG4-RD) and mucosa-associated lymphoid tissue (MALT) lymphoma (subsequently renamed extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue) [135,136].
CLASSIFICATION CRITERIA — In 2016, the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) jointly endorsed a new set of criteria for the classification of primary Sjögren’s disease (SjD) (table 2) derived through international consensus [124,137]. These and the multiple classification schemes for SjD that have been proposed since the 1980s [24,29,72,123,138,139] were developed for use in scientific communication and clinical research and not for diagnostic use in routine clinical practice.
Prior to the development and endorsement of the ACR/EULAR criteria, the most widely utilized criteria sets were those of the American-European Consensus Group (AECG), proposed in 2002 [72,138]. The AECG criteria set consisted of six items, both subjective and objective. Another set of criteria, consisting of only three objective items, was developed in 2012 for the purpose of classifying individuals for enrollment in clinical trials. These were developed using the Sjögren's International Collaborative Clinical Alliance (SICCA) registry, were provisionally approved by the ACR, and are known as the 2012 ACR classification criteria .
The ACR/EULAR criteria have features common to both the ACR and AECG criteria. They are an advancement over the 2002 and 2012 criteria sets, eliminating as criteria rarely performed salivary gland scintigraphy and parotid sialography, refining the autoantibody criterion to include only anti-Ro/SSA antibodies, and incorporating the new SICCA ocular surface staining scoring scheme, designed for ocular surface examinations that utilize both fluorescein and lissamine green as ocular surface dyes.
The 2016 ACR/EULAR classification criteria for primary SjD are based on a weighted scoring system, similar to those used for the classification of systemic sclerosis (scleroderma) and rheumatoid arthritis (table 2). They were derived from studies on individuals with primary SjD; they are thought to have equivalent applicability to patients with SjD associated with other autoimmune diseases (ie, secondary SjD), but this has not been studied.
The criteria can only be applied to an individual with at least one symptom of ocular or oral dryness (defined by a positive response to at least one of five questions [which were originally components of the AECG criteria]) or in whom there is suspicion of SjD based on glandular enlargement or the presence of characteristic extraglandular involvement (defined by a positive item in at least one domain of the EULAR SjD disease activity index) (table 3). (See "Overview of the management and prognosis of Sjögren's disease", section on 'Assessment of disease activity and severity'.)
An individual can be classified as having primary SjD if the total score is four or more. As was true for earlier criteria sets, an individual can only be classified as having primary SjD if they have either of the following two items (each with a score value of three points): relevant autoantibodies (anti-Ro/SSA in the 2016 ACR/EULAR criteria) or a labial salivary gland biopsy showing focal lymphocytic sialadenitis with a focus score ≥1. Other criteria, each worth one point, include an abnormal Schirmer test, low salivary flow rate, or high ocular surface staining score. Exclusion criteria include a past history of head and neck radiation treatment, active hepatitis C infection, acquired immunodeficiency syndrome (AIDS), sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related disease (IgG4-RD).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's 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 is the patient education article that is relevant to this topic. We encourage you to print or e-mail this topic 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.)
●Basics topics (see "Patient education: Sjögren's disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")
●Features that suggest possible SjD – The diagnosis of Sjögren’s disease (SjD) should be suspected in individuals with persistent symptoms of dry eyes and/or mouth, parotid gland enlargement, an unexplained increase in dental caries, or abnormal results of specific serologic tests (eg, anti-Ro/SSA and/or anti-La/SSB antibodies, rheumatoid factor, and hyperglobulinemia). (See 'Diagnostic criteria' above and 'Symptoms of dry eyes and mouth' above.)
●Diagnostic criteria – We make a diagnosis of SjD if the following two criteria are met and other causes of ocular and/or oral dryness have been excluded (see 'Diagnostic criteria' above and 'Diagnostic evaluation' above):
•Objective marker of dry eye or salivary hypofunction/characteristic MRI or ultrasound – The patient has an objective marker of dry eye (Schirmer test in either eye of <5 mm/5 minutes or abnormal ocular surface staining (picture 1 and figure 1A-B)) or salivary hypofunction (abnormal Saxon test or whole sialometry). Alternatively, the patient may have MRI (image 3) or ultrasound (US) (image 2) evidence of significant glandular parenchymal abnormalities characteristic of SjD.
•Characteristic autoantibodies or labial salivary gland biopsy or systemic autoimmune disease – The patient has anti-Ro/SSA antibodies with or without anti-La/SSB antibodies, a positive labial salivary gland biopsy (ie, focal lymphocytic sialadenitis with focus score ≥1) (image 4), or a well-established systemic rheumatic disease (eg, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis [scleroderma], or idiopathic inflammatory myopathy). Alternatively, the patient may have anticentromere antibodies (in the absence of systemic sclerosis) or the combination of an antinuclear antibody (ANA) ≥1:320 with a positive rheumatoid factor.
●Differential diagnosis – The differential diagnosis of SjD includes a broad range of conditions including dryness related to aging, medications, or environmental factors; autoimmune disorders such as systemic lupus erythematosus, which may sometimes be associated with SjD; immunoglobulin G4 (IgG4)-related disease (IgG4-RD); sarcoidosis; infection; and lymphoproliferative disorders (table 1). (See 'Differential diagnosis' above.)
●Role of classification criteria – Multiple classification schemes for SjD for use in scientific communication and clinical research have been proposed but were not developed for diagnostic use in routine clinical practice. In 2016, the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) jointly endorsed a new set of criteria for the classification of primary SjD derived through international consensus (table 2). (See 'Classification criteria' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.
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