Sjögren's syndrome in an out-patient clinic: classification of patients according to the preliminary European criteria and the proposed modified European criteria

J. G. Brun, T. M. Madland, C. B. Gjesdal and L.-T. Bertelsen

Department of Rheumatology, Haukeland University Hospital, N-5021 Bergen, Norway


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. To investigate whether out-patients with a clinical diagnosis of Sjögren's syndrome (SS) satisfied current preliminary European criteria for SS, and to determine the proportion of patients who satisfied the proposed modified European criteria for SS and thus had indication of an autoimmune process.

Methods. Out-patients with a clinical diagnosis of SS registered between 1 January 1999 and 1 November 2000 were included in the study.

Results. Of 203 patients with a clinical diagnosis of SS, 116 (57.1%) satisfied the current European criteria and 83 (40.9%) satisfied the proposed modified criteria.

Conclusions. Sicca symptoms and signs may have a variety of causes. In our study only 40.9% of the patients with a clinical diagnosis of SS satisfied the proposed modified European criteria and had evidence of SS as an autoimmune condition. Our findings indicate that for patient populations with an established diagnosis of SS according to the preliminary European criteria, approximately one-third will lose the diagnosis according to the modified criteria.

KEY WORDS: Sjögren's syndrome, Classification, Diagnosis, Autoimmunity.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Sjögren's syndrome (SS) has been defined as a slowly progressive autoimmune inflammatory disease affecting primarily the exocrine glands [1]. The disease exists as a separate rheumatic disease, or may be secondary to other systemic rheumatic diseases. No single test is sufficient for a diagnosis of SS [2]. In Norway, the preliminary European classification criteria for SS [3] are often used as a guide to diagnosis in the clinical setting [4]. These current criteria have been criticized because a patient may be classified as having SS without evidence of autoantibodies (SSA/SSB) or specific salivary gland inflammation, and thus have no indication of an autoimmune process. However, in the recently proposed modification of the European criteria, the presence of autoantibodies or salivary gland inflammation is obligatory [5]. This modification brings the European criteria closer to criteria used in the USA [6], and will simplify the understanding and comparison of studies on SS.

In the present study we investigated whether the clinical diagnosis of SS for our out-patients fulfilled the formal criteria, with special emphasis on the proportion of patients who satisfied the proposed modified criteria and thus have indication of an autoimmune process.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Out-patients registered with the ICD-10 code for SS (M35.0) from 1 January 1999 (date of introduction of the ICD-10 diagnostic system in our hospital) to 1 November 2000 were included in the study. The patients routinely had at least one visit per year, thus the majority of patients were included in the time period. The data were obtained from medical records retrospectively and included information up to and including the last visit registered with the code M35.0. Patients were excluded if the coding was observational (only meant as a temporary diagnosis of sicca symptoms, followed by a conclusion of no clinical diagnosis of SS), if they had secondary SS, if they were miscoded, or if they fulfilled exclusion criteria from the classification sets.

Sicca symptoms were usually described in the medical records as present or not present, without additional details. Except for those instances were it was clearly formulated that there were no such symptoms, or the symptoms clearly did not comply with criteria, the presence of sicca symptoms from the eyes or the mouth was accepted as fulfilling items I and/or II of the criteria sets.

A minor salivary gland biopsy was performed in 179 (88.2%) of the patients. With few exceptions the medical records had information about the Schirmer-I test (86.7%), unstimulated salivary flow (68.5%), and autoantibodies (99.5%). The cut-off levels for a positive rheumatoid factor (RF) and positive antinuclear antibodies (ANA) were set at titres of 128 [7, 8]. A positive Schirmer-I (wetting of <=5 mm in 5 min) for one eye was accepted as meeting the criteria. Only a minority of patients had Rose Bengal staining (48.3%) and salivary gland scintigraphy or sialography performed (16.3%). These investigations were generally performed following the other investigations if the diagnosis was perceived as still unclear.

The preliminary European criteria [3] are composed of six main items: ocular symptoms (I), oral symptoms (II), ocular signs, i.e. Schirmer-I test or Rose Bengal score (III), histopathology, i.e. focus score (IV), salivary gland involvement, i.e. scintigraphy, sialography or unstimulated salivary flow (V), and autoantibodies, i.e. RF, ANA, or antibodies to SSA or SSB (VI). Items I and II constitute the subjective criteria, while items III–VI constitute the more objective criteria. A positive response on any four items is sufficient for a diagnosis of SS. In the validation of these criteria, RF and ANA were excluded from item VI [3, 9]. ANA and RF are also excluded from item VI of the proposed modified European criteria [5]. In this set, any four criteria which include items V or VI are sufficient for a diagnosis of SS. In addition, any three of the objective criteria (items III–VI) are also sufficient for a diagnosis of SS.

Contingency table methods and t-tests were used in the statistical analyses. The two overlapping groups of SS patients (current or modified criteria) were each compared with the group of patients who had no SS according to any of the criteria sets. Variables not part of the criteria sets were analysed statistically.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The out-patients typically had between one and three consultations in the study period, yielding a total of 10720 consultations. Of these, 457 (4.3%) were coded M35.0, representing 287 individual patients. Eighty-four patients were excluded because of miscoding (n=21), secondary SS (n=13), observational diagnosis only (n=46), and fulfilment of exclusion criteria (n=4). The remaining 203 patients were coded correctly according to the clinical diagnosis in the medical records. The characteristics of this population are given in Tables 1Go and 2Go. One hundred and sixteen (57.1%) of the 203 patients identified satisfied the current preliminary European criteria, and 83 (40.9%) satisfied the proposed modified European criteria. Thirty-four (29.3%) of the 116 patients who met the current criteria lost the diagnosis of SS according to the modified criteria, while only one patient who did not previously satisfy criteria received the diagnosis. The frequency of positive criteria items for each diagnostic group is shown in Table 3Go.


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TABLE 1.  Characteristics of the patient groups. The two groups with SS overlap. Continuous variables; mean (± standard deviation)

 

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TABLE 2.  Characteristics of the patient groups. Discrete variables; number (%) of each diagnostic group positive for the characteristic

 

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TABLE 3.  Number (%) of each diagnostic group with a positive item from the criteria sets

 
Among the 34 patients who lost the diagnosis of SS according to the new criteria, three had a focus score of one or more, while none had antibodies to SSA or SSB. The one patient who received the diagnosis according to the new criteria, had three positive items in total (Schirmer-I test, focus score, antibodies to SSA/SSB).

Comparisons of the patients with SS (current or modified criteria) vs the patients with no SS according to any of the criteria sets, showed no significant differences regarding the male/female ratio, age, disease duration or clinical variables (Tables 1Go and 2Go). Both overlapping SS groups had significantly higher levels of IgG than the group with no SS. The group with SS according to the modified criteria also had significantly higher erythrocyte sedimentation rate (ESR) values than the group with no SS.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Sicca symptoms and signs may have a variety of causes, examples of which are age, drugs, viruses, non-specific sialadenitis, hypoplasia of salivary glands and sarcoidosis [1, 1012]. SS populations based on the comparatively non-specific preliminary European criteria may thus be heterogeneous, and many of the patients will have no indications of an autoimmune process. In addition, some patients with sicca symptoms and a positive biopsy and/or autoantibodies may not be included because of the minimum requirement of four criteria. In the proposed modification of the European criteria, a positive biopsy or autoantibodies to SSA/SSB is obligatory. Also, any three of the four objective criteria (items III–VI) are sufficient for a diagnosis. These modifications aim to increase the specificity of the criteria, and in some instances the sensitivity with regard to SS as an autoimmune disease. However, in our study only one patient changed status from not satisfying the current criteria to satisfying the modified criteria. On the other hand, the increase in specificity resulted in a 29.3% decrease in the patients formerly fulfilling the criteria.

We calculated the specificity and sensitivity of the old criteria, using the new proposed criteria as a gold standard for the diagnosis of primary SS. This resulted in a specificity of 71.1% and a sensitivity of 98.8% for the old criteria. Our findings thus indicate that for patients with an established diagnosis of SS who meet the current European criteria, the use of the modified criteria set will result in the loss of the diagnosis for approximately one-third of the patients. For population-based studies these figures may of course be different.

A validation of the preliminary European criteria was published in 1996 [9]. In this version, the sensitivity and specificity of the criteria set were marginally improved by excluding a positive RF or positive ANAs from item VI (autoantibodies). However, these modifications had little penetration in the guidance of our clinical diagnosis of SS, and we chose to use RF and ANA in the preliminary criteria set in the present study. As could be expected, separate analyses using the validated criteria set instead of the preliminary criteria set gave only small differences from the present results. In these analyses, 111 (54.7%) of the 203 patients met the validated criteria, as compared with the 116 (57.1%) who met the preliminary criteria.

The description of sicca symptoms in the medical records had little detail. Thus, some patients registered with sicca symptoms may not have met the subjective criteria (items I and II: ocular and oral symptoms) if questioned specifically according to these items. The percentages of patients fulfilling the current and modified criteria sets in our material must accordingly be considered as maximum assessments.

The symptoms of extraordinary fatigue and arthralgia had high prevalences in all groups (Table 2Go), consistent with the results of previous studies [13, 14]. Fatigue and the other symptomatic variables were not significantly associated with SS as defined by the criteria sets. Interestingly then, the group most homogeneous and with the strongest association with autoimmunity as defined by the modified criteria had no significant differences regarding the clinical variables.

Thirteen (4.5%) of the 287 patients initially identified had secondary SS and were excluded from the study. This percentage is not equivalent to the previously estimated prevalence of secondary SS (21%) among our patients [15]. However, as most of the patients with secondary SS were registered according to the primary diagnosis, they were not included among the initially identified patients in the present study.

Eighty-six patients did not meet any of the criteria sets, but were concluded to have SS in the medical records. However, the criteria sets have been constructed for use in clinical studies, and may not be appropriate in all instances in clinical practice. The clinical specialist may use the criteria as a guide, but should also perform a total assessment after taking all of the relevant information into consideration.

The proposed modified criteria set, if adopted by the scientific community, will lead to more homogeneous and comparable SS patient populations in research, and corresponds with present understanding of SS as an autoimmune-related systemic disease. Use of the modified set will probably influence current practice, making autoantibodies to SSA/SSB or focal sialadenitis a premise for the diagnosis of SS in the clinical setting.


    Acknowledgments
 
We gratefully acknowledge the work of Alf Marton Aksland on the hospital diagnostic code computer files. Analyses of serum autoantibodies were performed at the Department of Microbiology and Immunology, Haukeland University Hospital, Bergen, Norway. Assessments of the minor salivary gland biopsies were performed at the Department of Oral Pathology, Haukeland University Hospital, Bergen, Norway.


    Notes
 
Correspondence to: J. G. Brun. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 6 February 2001; revised version accepted 28 September 2001.



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