30.4Methodological Procedures to Develop Disease Status Criteria

To quantify a global clinical assessment in a clinical scoring system is a simplification of a complex intellectual process that an expert clinician is able to do by elaborating all of the patient’s physical, biological and imaging-related findings, by selecting only the relevant data, and eliciting those related to concomitant psychological status or different diseases. The selection of items to be included in a clinical scale can be done by using statistical procedures or on the basis of an expert consensus (Delphi method). In this latter case, an expert committee preliminarily chooses the variables that may predict a disease status. Construct validity, content validity, and sensitivity to change of the proposed scale are then verified in a sufficient number of true or simulated patients, with the physician’s global assessment generally considered to be the external criterion (gold standard). Conversely, the variables to be included in the scale can be selected and stratified for severity by analyzing a sufficiently large series of real patients and building a multivariate model in which the physician’s global assessment represents the dependent variable. Validation of this preliminary index should then be performed by using it on a different series of patients.

30.5Development of Disease Status Indices for Sjögren’s Syndrome

30.5.1The Italian Approach

The first study aimed at defining activity and damage criteria for SS was conducted out by an Italian group [20]. A methodology similar to that used to develop ECLAM (European Consensus Lupus Activity Measurement) was employed [21]. Two multivariate models based on data collected from a rather large of patients recruited in a number of Italian centers were built in order to select the variables predictive of disease activity and damage, respectively. The physician’s global scores, given by the observers in assessing both activity and damage, were used as dependent variables of the two multivariate linear models. The variables that significantly contributed to the definition of the two models were taken into account in the formulation of the two disease status scales: the SS Disease Damage Index (SSDDI) and SS Disease Activity Index (SSDAI). The weight of any variable in each scale was extrapolated by the correlation coefficient of the same variable in the corresponding model. The correlation between the scores for damage and activity obtained by applying SSDDI and SSDAI, respectively, and the scores assigned by the observers for the corresponding clinical status entities, was used to measure the construct validity of both indices. The ability of SSDAI to detect the variation of activity over time (sensitivity to change) was tested by applying SSDAI scale in two different observation times characterized by different levels of perceived activity.

Modified from Vitali et al. [21] with permission of John Wiley & Sons, Inc

The fact that SSDDI and SSDAI were built starting from a rather limited series of patients recruited in a single country may raise some doubts about their content validity. Therefore, the validity and reliability of these indices need to be verified in larger studies performed in different cohorts of patients collected on a multinational basis.

The SSDDI and SSDAI scoring systems are reported in Tables 30.1 and 30.2, respectively.

Table 30.2 SS disease activity index (SSDAI)

SSDAI

30.5.2The British Approach

At the same time as the Italian group, a British Group performed a similar study aimed at developing and validating an activity index for SS [22]. The proposed scale was based on a modified version of the BILAG (British Island Lupus Activity Group) index for systemic lupus [23]. The BILAG scoring system is a multidimensional nominal scale, in which eight domains are separately considered and scored for activity according to changes since the previous observation. Stratification of each domain of the index for severity is done according the observer’s intention to treat. An additional domain dedicated to specific features of SS was included in this BILAG-derived Sjögren’s Syndrome Clinical Activity Index (SCAI). Because the analysis of the correlation matrix showed that a number of variables were interrelated, this instrument was reduced to a six-factor model. A correlation between the physician’s global assessment and the SCAI derived score was used to test construct

validity of the index. Furthermore, sensitivity to change was tested by comparing SCAI-derived and physician-defined disease flares, even based on the intention to treat analysis. Content validity of SCAI, similar to what has been argued for SSDAI, may have some limitations, because this index was derived from the analysis of a limited cohort of patients recruited in a single country.

A modified version of Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) [18], adapted for the clinical peculiarities of SS, has been applied to lupus patients with secondary SS and patients with primary SS. This scale was shown to be a valid instrument for the measurement of some domains of disease damage related to sicca complaints [24]. Another version of SLICC/ACR-DI, with modifications included for specific use in SS, has been developed by a multidisciplinary British group. Specialists in rheumatology, ophthalmology, and oral medicine were part of the group. Ocular and oral domains and eight systemic domains represented the components of this new SS Damage Index (SSDI) [25]. A longitudinal study aimed at verifying the validity of this index in assessing cumulated damage of patients with SS is in an advanced phase.

30.5.3The EULAR Initiative

Because studies conducted solely on a national scale suffer from inherent potential limitations with regard to content validity and amplitude of data collection, a multinational initiative sponsored by EULAR (European League Against Rheumatism) has recently started. This is aimed at defining and validating a EULAR activity index for SS. A promoting committee that includes leading investigators from Europe and overseas. The conceptual framework of the project stemmed from idea that the spectrum of SS varies between two poles: (a) a stable or slowly progressive disorder limited to epithelial regions (principally exocrine glands), characterized clinically by sicca complaints and constitutional symptoms such as fatigue and musculoskeletal pain; and (b) a more aggressive and systemic disorder, accompanied by extra-epithelial features and serological signs of autoimmune activation.

With this statement in mind, the task force of the project decided that two indices are needed to correctly define activity in SS. The first index, termed the EULAR SS Patient Reported Index (ESSPRI), is devoted to the assessment of sicca complaints and subjective symptoms such as dryness, fatigue and pain from the perspective of the patient. The second index, known as the EULAR SS Disease Activity Index (ESSDAI), addresses global activity related to the systemic features of the disease.

The Delphi methodology was followed initially in the design of ESSDAI. On the basis of their clinical experience and of the present knowledge from the literature review, the Steering Committee members first selected the organor system-specific domains they considered relevant to disease activity, and, in each domain, defined and ranked for severity all the possible related items. This proposal was submitted to the expert panel, who were asked to suggest and approve possible changes.

The final derived scale was preliminarily validated using a cohort of 702 simulated cases constructed, by means of a computer-assisted program, from a series of

96 real patient vignettes initially provided by members of the Steering Committee. Using the whole cohort of true and simulated cases, a multivariate model was built in which the ESSDAI domains represented the independent variables and the physician’s global assessment, given by each expert to real and computer-derived clinical vignettes, was considered the dependent variable (gold standard). All of the domains listed in the ESSDAI were significantly associated with the physician’s disease activity perception in the multivariate model. Finally, construct validity was assessed by correlation between the ESSDAI and physician’s global scores [26].

Since the data on three consecutive visits (time 0, and after 3 and 6 months) for the 96 real patient profiles were available, it was possible to score these clinical vignettes in each observation time by applying both the ESSDAI and the previously described indices for activity (SSDAI and SCAI). Experts from the study group scored the same clinical vignettes in each observation time by simply judging whether disease activity had improved, worsened, or remained stable at visits 2 and 3 with respect to previous observation time. This procedure allowed testing sensitivity to change of the ESSDAI, SSDAI and SCAI and compare their performance in appreciating over time the variations of activity level. Analysis of performance characteristic curves, which Fig. 30.1 reports for the transition from visit 1 to visit 2,

a

Fig. 30.1 Performance characteristic curves of disease activity indexes for primary Sjögren’s syndrome. Plots show the relationship between a change in disease activity score (D score) and

the probability that the b expert judged this change as improved, stable, or

worsened, for ESSDAI (A), SSDAI (B), SCAI (C), and modified SCAI (D). In modified SCAI additional items were added to the original version, such as fatigue, myalgia, arthralgia, Raynaud’s phenomenon, shortness of breath, and pleuropericardial pain (Source: Seror et al. [27], with permission of John Wiley and Sons, Inc)

d

This kind of analysis showed that all scores discriminate improved and worsened disease activity effectively. However, the ESSDAI detected changes in activity and disease stability more accurately than the other indices [27].

The framework for ESSPRI development was consistently conditioned by the evidence that dryness, pain, and fatigue (somatic and mental) represent the key symptoms of patients with primary SS [28, 29]. These studies also indicated that a single numerical (or visual) scale for each domain is sufficient to assess these features. On the basis of this conceptual background, the preliminary ESSPRI was composed by specific questionnaires exploring these key symptoms of the disease. These questionnaires were applied in a large number of patients coming from different countries. A multiple regression model in which the patient’s global assessment was considered the dependent variable (gold standard) was analyzed to select the most relevant domains in the patient perception and estimate their weights. In this multivariate model, dryness, limb pain, and physical fatigue were significantly associated with patient’s global assessment, and weights derived from the regression were identical for these three domains. Thus, ESSPRI was redefined as a simple tool composed by three scales assessing the main symptoms, i.e., dryness, limb pain, and fatigue [30].