5.1Introduction

SjšgrenÕs syndrome (SS) is a common systemic autoimmune disease which primarily affects the salivary and lacrimal glands and usually leads to a persistent dryness of the mouth and eyes due to the lymphocytic inÞltration and functional impairment of the exocrine glands [1, 2]. The disease is commonly included in the spectrum of

C. Vitali ( )

Section of Rheumatology, Department of Internal Medicine, Villamarina Hospital, Piombino, Italy e-mail: c.vitali@yahoo.it

connective tissue diseases (CTDs) and, together with the other members of this disease family, it shares the possibility of a multisystemic involvement with a very large range of clinical and serological manifestations. Besides the diseasespeciÞc exocrine manifestations, SS may be, in fact, characterized by constitutional symptoms, arthritis, skin, lung, renal and neurological involvement as well as by the production of a plethora of autoantibodies [3].

As SSÑand CTDs in generalÑdoes not present a single distinguishing feature which can allow a correct diagnosis, the presence of a combination of clinical and laboratory manifestations is needed to identify the single disease, and all

these parameters have been collected in speciÞc and sensible classiÞcation criteria sets. The purpose of the classiÞcation criteria is to distinguish patients with a disease from patients without it and from normal subjects. Ideally, classiÞcation criteria should have high sensitivity to identify the particular disease they are created for and high speciÞcity to distinguish it from other similar diseases. Conceptually, classiÞcation criteria and diagnostic criteria could be considered equal (particularly when their sensitivity and speciÞcity are both close to 100%). However, classiÞcation criteria are usually not completely reliable and a certain percentage of patients can be misclassiÞed. So they do not represent the medical standing for a diagnosis and Þnally only the physician can make a proper diagnosis for an individual patient [4]. Therefore, classiÞcation criteria are intended to select patients for epidemiological, clinical, and therapeutic studies [4].

CTDs are chronic inßammatory diseases characterized by a relapsing remitting course. Each ßare of these diseases can be spontaneously remitted or reverted by a proper therapeutic approach. If this does not happen, irreversible damage can be caused in the involved organ or system.

Activity implies reversibility of the process and it is usually characterized by inßammatory manifestations in various organs or systems. Damage represents the component of the disease process that is irreversible and can be deÞned as the presence of a permanent loss of function or by radiographically or histologically evident structural derangement of the compromised organ or system [4]. For this reason, the clinical course of CTDs needs to be monitored by proper instruments which can precisely and correctly measure the phase of activity and the cumulated damage. SS is generally a relatively stable, slowly progressive CTD. Nonetheless, it does not elude these rules and a certain number of patients can develop activity ßares which can lead to acute involvement and to potential damage of various glandular and extraglandular organs.

Therefore, the distinction of clinical manifestations of the disease between features related to activity and those related to damage/chronicity, and the elaboration of the respective status

indexes is mandatory for SS. This has historically proven to be crucial in rheumatology, in particular for clinical research on systemic autoimmune diseases and therapeutic studies [5, 6].

5.2Comparison of the Different Classification Criteria Sets for Primary SS

Several classiÞcation criteria sets have been proposed for SjšgrenÕs syndrome (SS) over the years by leading experts in the Þeld, but none of them have been widely accepted in the scientiÞc community [7Ð9]. The traditional criteria sets most widely used in the past for the deÞnition of SS include the San Francisco criteria (proposed in 1975 and subsequently revised in 1984) [10, 11], the Copenhagen [12], the Japanese [13], the Greek [14], and the San Diego criteria, all proposed in 1986 [15]. The Japanese criteria have been subsequently updated over the years and the latest version was proposed in 1999 [9, 16].

Nearly all of them deÞned SS as an autoimmune exocrinopathy and therefore focused the efforts of the classiÞcation on the main organs involved: the lacrimal and salivary glands. Nonetheless, many important differences are appreciable when compared to each other. Table 5.1 focuses on their similarities and dissimilarities.

First, all of the criteria sets, except the Copenhagen one, used the terminology ÒprobableÓ and ÒdeÞniteÓ SS, while, only the Copenhagen and the Greek criteria used the terminology ÒprimaryÓ SS and ÒsecondaryÓ SS [12, 14]. Secondly, much argumentation and concerns have dealt with the discrepancy between including in the classiÞcation criteria sets either the subjective symptoms and the objective data or exclusively the easily reproducible objective Þndings. Thirdly, as far as ocular tests were concerned, comparing the different criteria sets, discrepancies emerged related to the tests used, the range and the cut-off levels of normal values, and the requirement of solely one abnormal test to allow the diagnosis of keratoconjunctivitis sicca (the Greek criteria) or at least two abnormal tests (the

San Francisco, Copenhagen, Japanese, and San Diego criteria) (see Table 5.1) [12Ð15].

Similarly, various objective methods have been employed in attempts to assess the salivary components of SS. Nearly all of the Þve criteria sets included salivary ßow rate estimation as a criterion for the diagnosis of SS salivary impairment. Sialometry was, nonetheless, performed by using different modalities. Even if both unstimulated and stimulated sialometry were not considered speciÞc tests, they appeared to be simple and non-invasive, and thus included in the criteria

as a crude assessment of the functional status of the salivary glands. Only the Japanese criteria used abnormal sialography as a criterion for salivary gland assessment in SS [13]. In contrast, the Copenhagen criteria employed salivary gland scintigraphy, which, even if rather expensive, provided a functional evaluation of all salivary glands [12]. All these criteria sets included the minor salivary gland biopsy. Both the Greek and the San Diego criteria considered the minor salivary gland biopsy to be mandatory with a focus score ≥2 as a crucial prerequisite for the

diagnosis of SS [14, 15]. On the contrary, the San Diego criteria speciÞed that an abnormal minor salivary gland biopsy was necessary only for ÒdeÞniteÓ SS, whereas the category of ÒprobableÓ SS could be fulÞlled in the absence of a biopsy [15]. According to the Copenhagen criteria, a patient could have been diagnosed as having SS without an abnormal salivary gland biopsy while, Þnally, according to the Japanese criteria, biopsy from tear glands could replace the minor salivary gland biopsy [12, 13]. As far as the modalities for performing the biopsy were concerned, all the criteria adopted the guidelines which had been previously proposed by Daniels et al. in 1975 [10], in which focal sialadenitis had been differentiated from chronic non-speciÞc sialadenitis, deÞning a focus as a cluster of at least 50 mononuclear cells. To diagnose primary SS, an average focus score per 4 mm2 was required, based on the evaluation of at least four glands. Moreover, according to Daniels the biopsy sample had to be obtained through clinically normal mucosa, and lobules characterized by non-speciÞc inÞltrates had to be excluded from the evaluation [10, 11]. The importance of focus sialadenitis was outlined by subsequent studies which conÞrmed that the histological criterion was highly associated with parotid ßow rate, diagnosis of keratoconjunctivitis sicca, and presence of anti-nuclear or anti-Ro antibodies [11, 16Ð18].

Finally, for the Þrst time, the San Diego criteria had utilized for the diagnosis of SS the presence of autoantibodies (anti-nuclear antibodies, anti-SS-A/Ro, anti-SS-B/La, and IgM-RF), pointing to the fact that the disease is autoimmune in origin [15].

Overall, in spite of their differences, these proposed classiÞcation criteria hypothetically could have been able to select and correctly classify patients affected by SS, when used by single groups of investigators. However, the major limitation of these criteria was that they had never been validated by multicenter studies or by means of standard statistical approaches, making impossible to carry out comparable epidemiological studies. Furthermore, in many cases, the sensitivity, speciÞcity, and reliability of the procedures followed for the deÞnition of the disease remained to be assessed.

5.3From the Preliminary European Criteria of the Epidemiology Committee of the Commission of the European Communities to the Revised Version of the European Criteria Proposed by the American–European Consensus Group

In view of the fact that previously proposed criteria did not achieve wide acceptance, in 1988 the Epidemiology Committee of the Commission of the European Communities decided to support a multicenter study to reach a consensus on classiÞcation criteria for SS [19]. The study began in 1989 and ended in 1993 with the deÞnition of the Preliminary European ClassiÞcation Criteria for SS [20]. It is noteworthy that for the Þrst time this study did not approach the problem using the Delphi method, which was based on the consensus of the experts, but used the same methodology and statistics which have been adopted by the American College of Rheumatology for rheumatoid arthritis (RA), deriving the criteria directly from a real patient cohort [20, 21] The European criteria were based on a six-item set and any four of these six items were considered to be required for the diagnosis. These items included (i) ocular symptoms, (ii) oral symptoms, (iii) ocular signs (deÞned by positive SchirmerÕs-I test and/or Rose Bengal score), (iv) signs of salivary gland involvement assed by parotid sialography, scintigraphy, and unstimulated salivary ßow, (v) focal sialadenitis observed in lip biopsy, and (vi) presence of autoantibodies. For primary SS, the presence of four out of six items had good sensitivity (93.5%) and speciÞcity (94%). Some exclusion criteria were also added to this classiÞcation set for SS, following the recommendations made by Fox et al. [15] and, namely, the presence of preexisting lymphoma, acquired immunodeÞciency syndrome, sarcoidosis, and graft-versus-host disease. The diagnosis of secondary SS could be made when in the presence of an associated CTD, and with the exclusion of the autoantibody item, three out of the remaining Þve items were met [20].

The criteria set was then validated in a following survey carried out on a different population of patients and controls. The six-item criteria conÞrmed it had a high sensitivity (97.5%) and speciÞcity (94.2%) [22].

After their validation, the European classiÞcation criteria achieved wide acceptance by the scientiÞc community in view of their accuracy. In fact, when previously proposed criteria [12Ð15] had been used to classify patients with primary SS and controls enrolled in the European study, they all showed a very high speciÞcity (range 97.9Ð100%) but a lower sensitivity (range 22.9Ð 72.2%). This could have run the risk of selecting particular subsets of patients [20]. Other potential advantageous characteristics of the European criteria were that they distinguished between primary SS and secondary SS but avoided the concept of deÞnite/possible SS. Nonetheless, the European criteria for the classiÞcation of SS generated extensive discussion. The key point of the debate was that these criteria could be fulÞlled in the absence of either autoantibodies or positive Þndings on labial salivary gland biopsy and then could also be met by patients with sicca symptoms but not strictly primary SS. Furthermore, a criteria set in which two out of the six items were devoted to subjective complaints could not allow a correct classiÞcation of the patients with SS but without symptoms [9, 23, 24].

To overcome these objections and broaden the acceptance of the European classiÞcation criteria, a joint effort was undertaken by the European Study Group on ClassiÞcation Criteria for SS and by a group of American experts. The analysis was performed by using a receiver operating characteristic (ROC) curve of the revised criteria. The curve was obtained by plotting the sensitivity and speciÞcity values calculated for each different combination of positive tests. Based on this ROC curve analysis, the condition Òpositivity of any four out of the six itemsÓ and the condition Òpositivity of four out of six items with the exclusion of the cases in which both serology and histopathology were negativeÓ showed the same accuracy (92.7%) which was the highest among those obtained by different combinations of positive items. However, the second condition

had a lower sensitivity (89.5% vs 97.4%) but a higher speciÞcity (95.2% vs 89.4%). The presence of any three of the four objective criteria items also showed a slightly lower accuracy (90.5%) but a speciÞcity of 95.2% and a sensitivity of 84.2%. This combination was also deemed reliable to correctly classify patients with primary SS. In conclusion, the AmericanÐ European Consensus Group, maintaining the previous European scheme of six items, introduced the obligatory rule that for a deÞnite diagnosis of SS either the minor salivary gland biopsy or serology had to be positive (see Table 5.2) [25]. Other modiÞcations were proposed and included in the European criteria set to make the item deÞnition more precise. In particular, it was speciÞed that SchirmerÕs-I test should be performed with standardized paper strips in unanesthetized closed eyes, following the European and the Japanese tradition. Moreover, as the Rose Bengal test is not available in many countries, other ocular dye scores (i.e., ßuorescein stain and Lissamine Green) were proposed. These modiÞed criteria also deÞned a positive minor salivary gland biopsy as the presence of at least one focus of lymphocytes, specifying that it/they had to be adjacent to normal-appearing mucous acini per 4 mm2 glandular tissue. In particular, it was decided to add hepatitis C virus (HCV) infection as an exclusion criterion, considering that the sicca symptoms observed in this kind of patient such as extrahepatic manifestations of the virus needed to be differentiated from primary SS (see Table 5.2) [26].

The AmericanÐEuropean Consensus Group criteria were published in 2002 and adopted as gold standard criteria in Europe and in the USA [25]. In 1999 the revised Japanese criteria for SjšgrenÕs syndrome, advocated by the Japanese Ministry of Welfare, had been elaborated as well [27]. Compared to the AmericanÐEuropean Consensus Group, the Japanese criteria did not include symptomatology as an item, although they stated that clinicians should be aware of the sicca symptoms. They only relied on objective test results and required at least two abnormal tests both for the diagnosis of keratoconjunctivitis sicca and xerostomia. Finally, positive