Classification Criteria for Sjögren’s Syndrome

1

General Concepts on Classification Criteria

Sjögren’s syndrome (SS) is a systemic autoimmune disease (SAD) that primarily affects the exocrine glands, predominantly the salivary and lachrymal glands, and leads to their functional impairment with consequent persistent dryness of the eye and mouth. The pathological hallmark of the disorder is a focal lympho-monocytic infiltration of the target tissue.

In addition to the disease-specific exocrine manifestations, SS is also characterized in most patients by the production of a variety of autoantibodies and by a systemic and multiorgan involvement, where constitutional symptoms, joint, skin, lung, renal, and neurological manifestations may be present. This justifies the inclusion of SS in the SAD family.

Similarly to what happens in all of the SADs, SS does not present itself with a single distinguishing feature that can allow a correct diagnosis. Hence only a certain number of specific clinical and laboratory features can lead to and confirm a correct diagnosis.

Theoretically, classification criteria and diagnostic criteria can be considered alike. This is particularly true when the sensitivity and specificity of the criteria are equal up to nearly 100%. However, the main purpose of the classification criteria is to distinguish patients with the disease from patients without and from normal subjects, thus to define homogeneous disease groups for clinical and epidemiological studies. Ideally, classification criteria should possess a high-level sensitivity in order to be able to identify the particular disease they are created for, and an equally high specificity, so as to avoid the inclusion of patients with other similar diseases. If they are not valid, participants without the disease may be included in the disease group, and participants with clear-cut disease may be excluded. Conversely, valid classification criteria facilitate the selection of cohorts of patients with a given disease to be enrolled in clinical trials and epidemiologic studies, thus allowing comparison of results across studies.

2

The Historical Sets of Classification Criteria Proposed Before the 1990s

Leading experts in the field proposed a number of classification criteria sets for SS before the 1990s. Most of these criteria sets were presented and discussed during the first International Symposium on SS, held in Copenhagen in 1986. These historical criteria sets include the San Francisco criteria (proposed in 1975 and subsequently revised in 1984 ) and the Copenhagen, Japanese, Greek, and San Diego criteria. The Japanese criteria have been subsequently updated and the latest version was proposed in 1999.

Nearly all of them were chiefly addressed to precisely define the involvement of the lachrymal and salivary glands; that is, the evidence of tear and saliva flow reduction, as well as the presence of superficial lesions of the conjunctival epithelial surface and abnormalities in salivary gland imaging.

An important discrepancy among the different criteria sets concerned the subjective symptoms of either dry eye or dry mouth. Some criteria sets gave prominence to them for diagnostic assessment, whereas others focused on more specific and reproducible objective findings ( Table 4.1 ). Moreover, other important differences concerned the tests included in the criteria sets, the cut-offs chosen for each test, and the number of tests needed for the diagnostic definition of either ocular or salivary involvement. The differences among the proposed criteria sets are shown in Table 4.1 . For instance, only the Japanese criteria took into account sialography as a criterion for salivary gland assessment in SS. Conversely, the Copenhagen criteria included salivary gland scintigraphy, an expensive method for a functional evaluation of all the major salivary glands.

All the criteria sets included minor salivary gland biopsy, but only the Greek and the San Diego criteria sets considered it to be mandatory to classify a patient as having SS. In the Japanese criteria set, the tear gland biopsy could replace the minor salivary gland biopsy.

As to the modalities for performing the biopsy, all of the criteria sets adopted the guidelines proposed by Daniels et al. in 1975, where a focal sialoadenitis was defined by the presence of focal infiltrates and a focus score (FS) as a cluster of at least 50 mononuclear cells. To diagnose primary SS, an average FS per 4 mm ² was required, based on the evaluation of at least four glands. However, the FS considered as indicative for a diagnosis of SS was not the same in all of the criteria sets (see Table 4.1 ).

Subsequent studies confirmed that the focal sialoadenitis, quantified by the FS, was closely associated with parotid flow rate, evidence of keratoconjunctivitis sicca (KCS), and the presence of autoantibodies. Significantly, the presence of autoantibodies (anti-nuclear antibodies [ANAs], anti-Ro/SSA, anti-La/SSB, and immunoglobulin (Ig) M–rheumatoid factor [RF]) as an additional diagnostic domain was introduced only in the San Diego criteria set. This pointed out the autoimmune origin of the disease.

Finally, all of the criteria sets except that from Copenhagen adopted the terms of “probable” and “definite” SS, whereas only the Copenhagen and Greek criteria distinguished the “primary” form of SS from the “secondary” one.

Although the proposed criteria sets were all hypothetically able to correctly classify patients with SS, their application was limited to single centers, and none of them was validated by multicenter studies in the following years. For many years, this has made it difficult to compare data from epidemiological, clinical, and serological studies carried out by different investigators who had adopted different classification criteria in the selection of patients.