Classification and diagnosis of Sjögren's syndrome-I
Robert Fox, MD, PhD
Paul Creamer, MD
INTRODUCTION — Sjögren's syndrome (SS) is a chronic inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. SS can exist as a primary disorder or as a condition in association with another well defined autoimmune process such as rheumatoid arthritis, systemic lupus erythematosus (SLE) or scleroderma. Its genetics and clinical features most closely resemble a subset of SLE patients.
Although primarily characterized by a particular form of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), this condition may affect a wide variety of organ systems including skin, lung, heart, kidney, neural and hematopoietic system. SS has many features in common with SLE, but also has certain distinct types of organ involvement such as hyperglobulinemic purpura, renal involvement due to interstitial nephritis, and an increased risk of lymphoma. In this regard, primary SS patients straddle the fence of "aggressive" lymphocytes that infiltrate tissues throughout the body in addition to their infiltration of the lacrimal/salivary glands.
At the other end of the diagnostic spectrum is the patient with symptoms of dry eyes, dry mouth, a low titer positive antinuclear antibody, and vague symptoms of fatigue, myalgia and cognitive dysfunction. Distinguishing patients with primary SS from those with fibromyalgia, and depression who have complaints of ocular and/or oral dryness (often exacerbated by medications with anti-cholinergic side effects) has been a challenge confronting those who develop classification criteria, conduct therapeutic trials, and provide clinical care.
This topic will review the classification, diagnosis, and epidemiology of SS. The clinical manifestations of SS, although mentioned here for diagnostic purposes, are discussed in detail separately, as are the pathogenesis and treatment. (See "Clinical manifestations of Sjögren's syndrome", and see "Pathogenesis of Sjögren's syndrome", and see "Treatment of Sjögren's syndrome-I").
HISTORY — The first description of SS is generally credited to Johann Mikulicz who, in 1892, described a 42 year old farmer with bilateral parotid and lacrimal gland enlargement associated with a small round cell infiltrate . Because the term "Mikulicz's syndrome" could encompass so many different entities including tuberculosis, other infections, sarcoidosis, and lymphoma, the term "Mikulicz syndrome" fell into disuse because it did not provide sufficient prognostic or therapeutic information . The term is still occasionally used to describe the histologic appearance of focal lymphocytic infiltrates on salivary gland biopsies. In 1933 the Danish ophthalmologist Henrik Sjögren described clinical and histologic findings in 19 women, 13 of whom had probable rheumatoid arthritis, with dry mouth and dry eyes. Sjögren introduced the term "keratoconjunctivitis sicca" (KCS) for the latter syndrome to distinguish it from dry eyes caused by lack of vitamin A ("xerophthalmia"). In 1953, Morgan and Castleman presented a case of Sjögren's syndrome in a clinical pathologic conference and rekindled interest in the symptom originally known as "Mikulicz's syndrome" and later termed Sjögren's syndrome . The clinical features of the disease as we currently recognize the syndrome in its overt form were outlined in 1956 by Bloch et al . There has been considerable debate about the classification criteria with milder forms of SS that are discussed below.
However, the basic issue of diagnostic difficulty present in 1956 continues until the present. In the absence of a characteristic etiologic agent, the syndrome is defined by its clinical and laboratory features. The ocular component (aqueous tear deficiency or keratoconjunctivitis sicca) is well defined by its clinical signs. However, quantitation of the oral component of dry mouth has been more difficult since symptoms of dryness are common and most physicians/patients are reluctant to recommend/undergo minor salivary gland biopsy. Perhaps because of the infrequency of with which biopsies are performed, tissue obtained may be inadequate, and pathologists not experienced in reading these samples may incorrectly interpret the findings . Although laboratory tests such as antinuclear antibodies (ANA) have proved helpful in diagnosis, the ANA are much more sensitive than they are specific [6-8]. These issues remain the core of the diagnostic dilemma surrounding SS.
AMERICAN-EUROPEAN CLASSIFICATION CRITERIA — Classification criteria for use in scientific communication and clinical research have evolved. Criteria have been proposed by a group of American and European rheumatologists to serve as international criteria for classification of SS [9,10]. These criteria were not developed for use in routine clinical practice and not every patient who receives a clinical diagnosis of SS will fulfill the proposed criteria (See "Diagnosis" below). In addition, disorders that can be confused with SS must be excluded before a patient can be classified as having SS (See "Exclusion criteria" below).
These consensus criteria combine subjective symptoms of dry eye and dry mouth with objective signs of xerophthalmia (Schirmer's test, Rose Bengal or lissamine green staining) that can be easily performed at the time of the examination. Although the ophthalmologist may be best suited to perform these in conjunction with slit-lamp examination, these tests can be done without biomicroscopy. Additional confirmatory tests for oral dryness require laboratory evaluation. However, the requirement in the consensus criteria for either a characteristic minor salivary gland biopsy or a characteristic autoantibody (such as anti-Sjögren's syndrome-A antibody [anti-Ro/SSA] and anti-La/SSB) help distinguish the dryness of SS (an autoimmune syndrome) from other causes of dryness.
Rules for classification based upon the number and type of criteria satisfied are presented following the discussion of the items and listing of the individual criteria (see "Rules for classification" below).
Criteria — The consensus criteria are divided into six "items" . Each item has a set of from one to three defining criteria. An item is considered present if any one of the criteria included in its set is present. The "items" are the following:
• Ocular symptoms of inadequate tear production
• Oral symptoms of decreased saliva production
• Ocular signs of corneal damage due to inadequate tearing
• Salivary gland histopathology demonstrating foci of lymphocytes
• Tests indicating impaired salivary gland function
• Presence of autoantibodies (anti-Ro/SSA, anti-La/SSB, or both)
Ocular symptoms — The presence of dry eyes may be sought with questions such as: "Do you often feel a gritty or sandy sensation in your eyes?"  or "Have you had daily, persistent troublesome dry eyes for more than three months?" . Keratoconjunctivitis sicca is one cause of dry eyes. It is characterized primarily by a deficiency in aqueous tear production; other causes result from mucin deficiency (eg, due to lack of vitamin A), blepharitis due to Meibomian gland dysfunction, or excessive evaporation from the ocular surface (as in working for many hours in front of a computer monitor in a low humidity environment) . Use of a tear substitute more than three times daily, even in the absence of complaints of ocular dryness, is acceptable to meet the criterion of having symptoms of dry eyes.
Oral symptoms — The presence of dryness of the mouth and oral cavity may be revealed by questions such as "Do you wake up at night feeling so dry that you have to drink water?" or "Do you frequently drink liquids to aid in swallowing dry foods?" .
Objective evidence of dry eyes — Tear production may be measured using the Schirmer test. A small piece of sterile filter paper, which comes in a standard Schirmer test kit, is placed in the lateral third of the lower eyelid and the extent of wetting in a given time is measured . Wetting of less than 5 mm in five minutes is considered abnormal. Use of topical anesthesia and blotting of the tear reservoir prior to the test may improve accuracy as a measure of basal tear production. The amount of wetting is typically symmetrical.
End organ damage to conjunctival and corneal epithelial cells may be measured by Rose Bengal, which stains areas of devitalized tissue. 10 µL of 1 percent Rose Bengal is instilled into the inferior fornix of the unanesthetized eye, the patient blinks twice, then the extent of staining of conjunctiva and cornea is scored [15,16]. Scoring damage in three regions of the eyes requires slit lamp examination, although some measure of staining can be obtained with an ophthalmoscope.
Other tests include the measurement of tear film instability by measuring breakup time after instillation of fluorescein, and measurement of tear osmolality as an indication of evaporation from the ocular surface . Tear film breakup, like Rose Bengal staining, requires slit lamp examination and both are therefore more likely to be performed by ophthalmologists.
Salivary gland biopsy — A labial salivary gland biopsy (LGB) can be an important diagnostic tool in patients with suspected SS. The biopsy should be taken from a macroscopically normal, nontraumatized part of the lower lip and should be large enough to contain at least four lobules. The key histologic feature is focal collections of lymphocytes, often beginning centrally within the lobule. The most widely accepted grading system records the number of foci of lymphoid tissue, defined as collections of 50 or more lymphocytes per 4 mm2 [17,18]. Most criteria require more than one focus per 4 mm2 for a definitive diagnosis of SS. Immunocytology shows most of the lymphocytes are CD4+ T cells 2 (see "Pathogenesis of Sjögren's syndrome").
There is some disagreement about the specificity and sensitivity of LGB for SS . Some patients with apparently classic SS do not show typical histology, a problem that may be due to sampling error. On the other hand, SS-like findings have been reported in other connective tissue disorders and in normal elderly subjects . Quantitative immunohistology may improve the specificity for SS . Another approach to improve the accuracy of LGB is to calculate a cumulative focus score by examining several sections separated by at least 200 µM . When compared to a focus score calculated from one section only, the multisection approach improved specificity of LGB from 84.5 percent to 94.4 percent without any change in sensitivity (93.9 percent).
Certain pathologic features, such as parenchymal atrophy and fibrosis, sometimes with scattered lymphoid cells, are almost universal in the elderly [22,23] and thus, should be excluded from any set of diagnostic criteria for SS. However, as long as focal collections of lymphocytes rather than diffuse scatterings are considered, most authors believe LGB to be the most specific method of confirming the diagnosis of SS  and, hence, the closest we have to a "gold standard."
Indications for performing a lip gland biopsy depend upon the patient population and the availability of expert biopsy and histopathology services . Indications for LGB  might include:
• Confirmation of a suspected diagnosis of SS, especially when it is critical to make the diagnosis as, for example, when systemic or extraglandular features are present
• Exclusion of other conditions that can cause xerostomia and bilateral gland enlargement (see "Differential diagnosis" below)
The pathology report should document an adequate number of evaluable intact lobules (at least 4) in the specimen, and the average focus score is optimally based on examination of at least 4 lobules . Lobules that have been ruptured due to non-immune mechanisms (eg, sialadenitis [inflammation of salivary gland], leading to rupture of ducts that release mucus), need to be discarded from the quantitation of the focus score .
Objective evidence of salivary gland involvement other than biopsy — To satisfy this item for salivary gland involvement an abnormal result of one of the three following tests is required: technetium excretion radionucleotide scanning (salivary gland scintigraphy), parotid sialography, or unstimulated production of saliva (whole sialometry < 1.5 mL per 15 minutes).
• Salivary gland scintigraphy — Quantitative salivary gland scintigraphy  which gives a dynamic picture of the function of all major salivary glands. The finding of very low uptake of the radionuclide, to the extent that discharge of tracer via the salivary ductal system can not be assessed, is a highly specific for SS but relatively insensitive finding (present in about one-third of SS patients) using this technique . Potential drawbacks to the use of salivary scintigraphy are lack of experience in performing and interpreting the test results and the inability to perform the test in the office setting.
• Parotid sialography — Parotid sialography is performed by retrograde cannulation of the major salivary gland ducts followed by instillation of an oil based contrast material. Although this method gives excellent visualization of the ducts (including a punctate sialadenitis), it is limited by the risk of rupturing the duct and should not be performed during an episode of acute parotitis [29,30]. A comparison of parotid scintigraphy and retrograde sialography suggests that the former method has better correlation with parotid function . Interpretation of sialography requires both training and experience . Unless someone with expertise in performing and interpreting sialography is available, another objective test of salivary gland integrity and/or function is preferred.
• Sialometry — Sialometry is the measurement of the rate of saliva production. The unstimulated whole salivary flow rate is a relatively simple test and avoids the need for special equipment or agents (such as citric acid) that are used for testing stimulated flow, or the production of saliva by just one parotid gland.
The patient is asked to expectorate once, then to collect all saliva into a graduated container. After 15 minutes the volume of saliva is measured. A collection of < 1.5 mL during this time is abnormally low.
Exclusion criteria — Patients who would otherwise fulfill the classification criteria, are excluded if one of the following disorders is present :
• Prior head and/or neck irradiation
• Infection with hepatitis C virus
• Acquired immunodeficiency disease (AIDS)
• Pre-existing lymphoma
• Graft versus host disease
• Recent use of drugs with anticholinergic properties
Rules for classification — The American-European consensus proposed rules for classification of patients based on the criteria are as follows :
• Primary Sjögren's syndrome — For patients with no associated connective tissue or autoimmune disease (eg, RA, SLE) and no exclusionary diagnoses (see "Exclusion criteria" above) a classification of primary SS is made according to the consensus rules in one of the three following ways :
1. The patient has either a positive salivary gland biopsy result or autoantibodies, and satisfies a total of 4 of the six items (sensitivity 97 percent, specificity 90 percent).
2. Alternatively, the patient satisfies three of the four objective items (ocular signs, biopsy, salivary gland involvement, or autoantibodies). This rule had sensitivity of 84 percent and specificity of 95 percent.
3. Finally, a classification tree with sensitivity of 96 percent and specificity of 94 percent can be used to determine whether or not patients are classified as having primary SS.
• Secondary Sjögren's syndrome — A classification of secondary SS is made according to the consensus rules if a "well defined" connective tissue disease is present and at least one symptom item (indicative of ocular or oral dryness) and any two of the three objective items exclusive of autoantibodies (ie, ocular signs, biopsy, or tests of salivary gland involvement other than biopsy) are present.
The remainder of this discussion of the classification and diagnosis of Sjögren's syndrome is continued separately. (See "Classification and diagnosis of Sjögren's syndrome-II").
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