ARTHRITIS & RHEUMATISM

Vol. 56, No. 7, July 2007, pp 2223–2231

DOI 10.1002/art.22658
© 2007, American College of Rheumatology

Sjögren’s Syndrome Disease Damage Index

and Disease Activity Index

Scoring Systems for the Assessment of Disease Damage and Disease Activity in
Sjögren’s Syndrome, Derived From an Analysis of a Cohort of Italian Patients

Claudio Vitali,1 Gianluigi Palombi,1 Chiara Baldini,2 Maurizio Benucci,3 Stefano Bombardieri,2
Michele Covelli,4 Nicoletta Del Papa,5 Salvatore De Vita,6 Oscar Epis,7 Franco Franceschini,8
Roberto Gerli,9 Marcello Govoni,10 Susanna Maddali Bongi,11 Wanda Maglione,5
Sergio Migliaresi,12 Carlomaurizio Montecucco,7 Maddalena Orefice,12 Roberta Priori,13
Antonio Tavoni,2 and Guido Valesini13

Objective. To develop valid instruments for the
assessment of disease-related damage and disease ac-
tivity in Sjögren’s syndrome (SS).
Methods. Data on 206 patients with primary SS
were collected in 12 Italian centers. Each patient was
scored by 1 investigator, on the basis of a global
assessment of the degree of disease damage and disease
activity. Patients judged to have active disease at the
time of enrollment underwent a second evaluation after
3 months. Univariate and multivariate analyses were
Presented in part at the 70th Annual Scientific Meeting of the
American College of Rheumatology, Washington, DC, November
2006.
Supported by the Scientific Committee of the Italian Society
of Rheumatology.
1
Claudio Vitali, MD, Gianluigi Palombi, MD: Villamarina
Hospital, Piombino, Italy; 2Chiara Baldini, MD, Stefano Bombardieri,
MD, Antonio Tavoni, MD: University of Pisa, Pisa, Italy; 3Maurizio
Benucci, MD: San Giovanni di Dio Hospital, Florence, Italy; 4Michele
Covelli, MD: University of Bari, Bari, Italy; 5Nicoletta Del Papa, MD,
Wanda Maglione, MD: G. Pini Hospital, Milan, Italy; 6Salvatore De
Vita, MD: University of Udine, Udine, Italy; 7Oscar Epis, MD,
Carlomaurizio Montecucco, MD: University of Pavia, Pavia, Italy;
8
Franco Franceschini, MD: Ospedali Civili, Brescia, Italy; 9Roberto
Gerli, MD: University of Perugia, Perugia, Italy; 10Marcello Govoni,
MD: University of Ferrara, Ferrara, Italy; 11Susanna Maddali Bongi,
MD: University of Florence, Florence, Italy; 12Sergio Migliaresi, MD,
Maddalena Orefice, MD: 2nd University of Naples, Naples, Italy;
13
Roberta Priori, MD, Guido Valesini, MD: La Sapienza University,
Rome, Italy.
Address correspondence and reprint requests to Claudio
Vitali, MD, Department of Internal Medicine, Rheumatology Section,
Villamarina Hospital, Via Forlanini 23, 57025 Piombino, Italy. E-mail:
c.vitali@yahoo.it.
Submitted for publication October 24, 2006; accepted in
revised form March 22, 2007.
2223
performed to select the clinical and serologic variables
that were the best predictors of damage and of disease
activity, and these variables were used to construct the
Sjögren’s Syndrome Disease Damage Index (SSDDI)
and the Sjögren’s Syndrome Disease Activity Index
(SSDAI). The weight of each variable in the index was
determined by the ␤ coefficients in multivariate regres-
sion models. Scores obtained using the SSDDI and the
SSDAI were compared with scores initially given by the
investigators. Finally, a receiver operating characteris-
tic (ROC) curve was used to determine the cutoff value
in the SSDAI with the highest level of accuracy in
identifying patients with a significant level of disease
activity.
Results. A multivariate model with 9 variables
was the best predictor of investigator scores of damage.
The scores obtained using the SSDDI were closely
correlated with investigator ratings (R ⴝ 0.760, P <
0.0001). A model composed of 11 variables was the best
predictor of investigator scores of disease activity. The
scores obtained using the SSDAI were strongly corre-
lated with the investigator ratings both at the time of
enrollment and 3 months after enrollment (R ⴝ 0.872,
P < 0.0001, and R ⴝ 0.817, P < 0.0001, respectively).
The differences between scores given by investigators at
study enrollment and after 3 months, a measure of
variation of disease activity over time, were also closely
correlated with the differences calculated using the
SSDAI (R ⴝ 0.683, P < 0.0001). The ROC curve
analysis showed that patients with the highest level of
2224
disease activity could be identified on the basis of an
SSDAI score of >5.
Conclusion. Our findings indicate that the SSDDI
is an adequate instrument to objectively measure dam-
age in patients with SS, and that the SSDAI is a valid
tool to measure disease activity when used either as a
single-state index or as a transition index.
The clinical course of the connective tissue dis-
eases (CTDs) is characterized by spontaneous flares in
which the underlying immunologic and inflammatory
mechanisms become more active. These activity phases
sometimes spontaneously reverse or, more often, are
completely or partially reversed by appropriate treat-
ment. When this reversal does not occur, a certain
degree of irreversible damage in the involved tissue or
organs, with consequent functional impairment, may
result from each disease flare. However, the side effects
of treatment can also induce irreversible damage in
patients with these diseases (1,2).
In the absence of specific clinical or biologic
markers that can be used to precisely assess the degree
of activity or damage in each specific disorder, disease
status criteria have been developed for many of the
CTDs, and are currently in use in experimental studies
and clinical care (3). In particular, several sets of disease
activity criteria have been proposed and validated for
systemic lupus erythematosus (SLE) (4–8), rheumatoid
arthritis (RA) (9–11), and systemic sclerosis (SSc) (12).
Similarly, the degree of damage in SLE can be assessed
by a specifically constructed index (13), while articular
damage in RA is usually measured using standardized
radiologic evaluation methods (14–16).
Sjögren’s syndrome (SS), which is classically in-
cluded among the CTDs, has also been defined as
autoimmune exocrinopathy (17). In SS, chronic lympho-
cytic infiltrates are present in multiple exocrine glands,
particularly salivary and lacrimal glands (18), and this
typically leads to a progressive loss of gland function.
However, extraglandular systemic features, defined as
clinical manifestations due to involvement of nonexo-
crine organs and tissue, are also present in most patients
with primary SS (19). These include Raynaud’s phenom-
enon, arthritis, vasculitis, leukopenia, renal and pulmo-
nary manifestations, peripheral neuropathy, and central
nervous system involvement. In addition, in some pa-
tients, the clinical course can be marked by a high degree
of disease activity in the early stage or, less often, the
late stage, characterized by glandular or systemic mani-
festations, or both (20). This can lead to irreversible
damage in the involved organs or tissue.
VITALI ET AL
No instruments have yet been developed to assess
disease activity or disease-related damage in SS. The
present study was undertaken to construct indices to
define and measure disease damage and disease activity
in SS. To this end, data from a large cohort of Italian
patients with primary SS were collected and then ana-
lyzed in order to select the individual clinical variables
and the combination of variables that represent the most
valid predictors of damage and disease activity.
PATIENTS AND METHODS
Data collection. Twelve Italian centers participated in
the study from February 2004 to May 2006. In each center a
single investigator who had extensive experience with patients
with SS was nominated to be responsible for selecting patients
and collecting data. These investigators took part in a prelim-
inary meeting, where they discussed the study protocol and
received training on the concepts of disease-related damage
and disease activity. The SS Study Group prepared study
outlines and a glossary in which each symptom, sign, and
laboratory test was precisely defined as specified in the Amer-
ican College of Rheumatology (formerly, the American Rheu-
matism Association) dictionary (21,22), and other accepted
references (23,24).
Investigators from each center were invited to select
patients with primary SS, based on the American–European
Consensus Group criteria (25). In at least 50% of the patients
enrolled in the study, disease had to be active to some degree.
Therefore, investigators enrolled consecutive patients at the
beginning of the study and, if most of the patients had inactive
disease, preferentially included patients with active disease in
the second part of the study recruitment period. Investigators
judged the level of disease activity in each patient on the basis
of clinical experience, and according to the instructions pro-
vided in the study protocol guidelines and clarified during the
preliminary educational meeting. Informed consent was ob-
tained from each enrolled patient.
Patients who were classified as having active disease at
the time of enrollment were evaluated a second time by the
same investigator after 3 months. This time interval was
established during study protocol preparation, based on the
general clinical experience that most clinical manifestations,
which are usually believed to be indicative of disease activity,
may be responsive to newly introduced therapeutic measures
within this time period.
A clinical chart, in which all patient demographic,
clinical, and laboratory data were recorded, was prepared by
the senior investigators of the SS Study Group. The clinical
chart was divided into 4 sections. Demographic data were
recorded in section I, classification criteria that were met by
the patient were recorded in section II, clinical and laboratory
data obtained at the time of study enrollment were recorded in
section III, and, for patients who were judged to have active
disease at the first clinical evaluation, clinical and laboratory
data obtained at the second evaluation were recorded in
section IV.
Investigators evaluated a total of 108 items, which were
INDICES OF DISEASE DAMAGE AND DISEASE ACTIVITY IN SS
classified into 15 groups according to the affected organ or
system. In each group, the clinical manifestations that could be
considered reversible and potentially related to an active
evolving process were distinguished from items indicative of
irreversible features, defined as stable results of past processes
that were no longer active. For each reversible item, investi-
gators specified whether it was the same, had improved, had
worsened, or had newly appeared with respect to the most
recent clinical observation prior to study enrollment. In con-
trast, the simple dichotomy of presence or absence was used to
describe irreversible items.
“Gold standards” for disease damage and disease
activity. In order to develop indices for both disease damage
and disease activity, external standards were needed. Investi-
gators in each center were therefore asked to classify the
enrolled patients according to their levels of accumulated
disease damage and present disease activity at each observa-
tion time. For this purpose, investigators used both a nominal
scale and a numerical scale. Using the nominal scale, accumu-
lated disease damage was classified as absent, mild/moderate,
quite severe, or very severe in each patient, and disease activity
was classified as inactive, mildly/moderately active, active, or
very active. In addition, each patient was scored for both
disease damage and disease activity on a numerical scale of 0
(no damage or no activity) to 10 (maximum possible level of
disease damage or disease activity). The study protocol stipu-
lated that the highest degree of damage (or disease activity)
that each investigator had previously observed when following
up patients with SS should be considered the maximum level.
Statistical analysis. The data recorded in the clinical
charts were entered into a database (Microsoft Access 2000;
Microsoft, Redmond, WA), using an electronic copy of the
chart, and then transferred into SPSS, version 11.0.3 (SPSS,
Chicago, IL). Univariate analyses were performed to select the
single variables (signs, symptoms, or results of laboratory or
other tests) that showed significant association with higher
classes or scores of disease damage and disease activity.
Multiple linear regression analyses were then carried out to
evaluate the combined performance of different regression
models (which included the single variables selected by univar-
iate analysis) in predicting the disease damage or disease
activity scores initially given by the investigators.
Once the multivariate models with the best perfor-
mance in predicting the degree of disease damage and disease
activity were selected, the 2 scoring systems, the Sjögren’s
Syndrome Disease Damage Index (SSDDI) and the Sjögren’s
Syndrome Disease Activity Index (SSDAI), were tentatively
constructed. The points assigned to any single variable in the
scoring systems were derived using the ␤ coefficients in the
multivariate models. The SSDDI and the SSDAI were used to
recalculate scores for damage and activity in all of the patients.
The strength of correlation between the SSDDI-derived score
and the damage score assigned by the investigator, and be-
tween the SSDAI-derived score and the disease activity score
assigned by the investigator, was taken into account as a
measure of the construct validity of the SSDDI and of the
SSDAI, respectively. However, the construct validity of each
index was also tested by assessing convergent and divergent
validity. This was determined by measuring the strength of
correlation of each variable in the SSDDI and in the SSDAI
with the corresponding standard (investigator ratings of dis-
2225
ease damage for the SSDDI and investigator ratings of disease
activity for the SSDAI) and noncorresponding standard
(investigator ratings of disease activity for the SSDDI and
investigator ratings of disease damage for the SSDAI). Non-
parametric methods such as Kendall’s tau-b and the
Kolmogorov-Smirnov Z test were used for this purpose.
The degree of agreement between the measures of
disease damage and disease activity derived by the SSDDI and
the SSDAI, respectively, and the corresponding investigator
ratings was tested by analyzing the normality of the distribu-
tion of their differences by means of the Shapiro-Wilk statistic
(W) (26). This is considered the most powerful test for
normality, and it estimates, using analysis of variance, the
deviation from Gaussian distribution for the same sample size.
The derived W value reflects the proportion of variance
explained by idealized Gaussian distribution. W values closest
to 0 indicate a more extreme departure from normal distribu-
tion, while those closest to 1.0 indicate an almost complete
identity with the Gaussian curve. The mean ⫾ SD differences
were also used to define the limit for 95% agreement between
the disease damage and disease activity scores assigned by
investigators and those derived using the indices (27), with
differences more than 2 SD above or below the mean consid-
ered to be outside the limit for 95% agreement.
The comparison between the investigator ratings and
index scores, made by analyzing the simple regression models
and the distribution of differences, allowed us to reconsider
some variables that did not contribute significantly to the
multivariate analysis but improved the validity of the con-
structed index when included among the listed items. The
analysis of the distribution of differences in patients from the
different centers also allowed us to evaluate whether the levels
of disease damage and disease activity were homogeneously
assessed. Finally, a receiver operating characteristic (ROC)
curve was designed to assess the efficiency of the SSDAI in
distinguishing patients with active or very active disease from
those with inactive or mildly/moderately active disease, as
initially defined by the investigator.
RESULTS
Demographic and clinical data. A total of 206
patients (5 men and 201 women) with primary SS were
enrolled in the study. The median age of the patients was
56.5 years (range 19–85 years), and their median disease
duration was 6 years (range 1–45 years). At least 1
extraglandular systemic feature was present in 85.9% of
the patients, and ⱖ2 of these features were present in
31.5% of the patients. The prevalence of systemic man-
ifestations was probably influenced by the method of
patient selection, which favored the inclusion of patients
with some degree of disease activity. Patients who were
judged to have some degree of disease activity at study
enrollment (n ⫽ 121) underwent a second clinical eval-
uation carried out by the same investigator ⬃3 months
after the first evaluation.
2226 VITALI ET AL

Table 1. Multiple linear regression model of disease damage in the relative score assigned to each. For each item the
patients with Sjögren’s syndrome* definition that was used in the study glossary is also
Independent variable ␤ t P shown.
Lymphoproliferative disease 0.425 9.395 0.000 The scores obtained using the SSDDI in all of the
Pleuropulmonary damage 0.339 7.133 0.000 patients were closely correlated with the scores given by
Tear flow impairment 0.257 5.602 0.000
CNS involvement (long-lasting) 0.158 3.428 0.001 the investigators (R ⫽ 0.760, P ⬍ 0.0001) (Figure 1).
Salivary flow impairment 0.146 3.169 0.002 The differences between the 2 scores were normally
Structural ocular damage 0.146 3.021 0.003 distributed (W ⫽ 0.94, P ⬍ 0.0001). The mean difference
Irreversible renal impairment 0.142 3.056 0.003
Loss of teeth 0.125 2.630 0.009 was close to 0 (mean ⫾ SD 0.267 ⫾ 1.31), and the
Peripheral neuropathy 0.115 2.451 0.015 differences were ⫾3, and therefore outside the limit for
* The dependent variable in this model was the numerical score for 95% agreement (see Patients and Methods), in only
disease damage (0–10) assigned by the investigator. This 9-item model 6.3% of the patients.
was a significant predictor of disease damage (R ⫽ 0.778, P ⬍ 0.0001).
CNS ⫽ central nervous system.
Construct validity of the SSDDI was also proven
by assessment of its convergent validity and divergent
validity. All of the variables included in the SSDDI were
SSDDI construction and validation. A multivar- closely correlated with the corresponding gold standard,
iate model with 9 variables was the best predictor of the i.e., the investigator scores of damage (P ⫽ 0.002 for 1
level of accumulated disease damage in the study pop- variable and P ⬍ 0.0001 for the remaining variables).
ulation. The variables included in this model, their ␤ The SSDDI variables either were not correlated with or
values, and their P values are shown in Table 1. Table 2 were weakly correlated with the gold standard for activ-
shows the variables included in the SSDDI and the ity, i.e., the investigator scores of activity.

Table 2. Sjögren’s Syndrome Disease Damage Index*

Item Definition Score
Oral/salivary damage
Salivary flow impairment Unstimulated whole saliva collection ⬍1.5 ml/15 minutes, 1
by standard method†
Loss of teeth Complete or almost complete 1
Ocular damage
Tear flow impairment Schirmer I test ⬍5 mm in 5 minutes, by standard 1
method†
Structural abnormalities Corneal ulcers, cataracts, chronic blepharitis 1
Neurologic damage
CNS involvement Long-lasting stable CNS involvement 2
Peripheral neuropathy Long-lasting stable peripheral or autonomic system 1
impairment
Pleuropulmonary damage (any of the following) 2
Pleural fibrosis Confirmed by imaging
Interstitial fibrosis Confirmed by imaging
Significant irreversible functional damage Confirmed by spirometry
Renal impairment (any of the following) 2
Increased serum creatinine level or reduced Long-lasting stable abnormalities
GFR
Tubular acidosis Urinary pH ⬎6 and serum bicarbonate ⬍15 mmoles/liter
in 2 consecutive tests
Nephrocalcinosis Confirmed by imaging
Lymphoproliferative disease (any of the 5
following)
B cell lymphoma Clinically and histologically confirmed
Multiple myeloma Clinically and histologically confirmed
Waldenström’s macroglobulinemia Clinically and histologically confirmed

* The index was constructed using variables selected by means of a multivariate linear regression model. The score value
assigned to each item was derived from the weight that the corresponding variable had in the model (␤ coefficient shown in
Table 1). The definitions shown were provided in the glossary included with the clinical chart in which patient data were
recorded. CNS ⫽ central nervous system; GFR ⫽ glomerular filtration rate.
† Refs. 24 and 25.
INDICES OF DISEASE DAMAGE AND DISEASE ACTIVITY IN SS 2227

scores at study enrollment were also normally distrib-

uted (W ⫽ 0.927, P ⬍ 0.0001).
Construct validity of the SSDAI was confirmed
by analysis of its convergent validity and divergent
validity. All of the variables that composed the SSDAI
were closely correlated with the corresponding gold
standard, i.e., investigator ratings of activity (P ⫽ 0.001
for 2 variables and P ⬍ 0.0001 for the remaining
variables). The SSDAI variables either were not corre-
lated with or were weakly correlated with the gold
standard for damage, i.e., the investigator ratings of
damage.
The validity of the SSDAI as a single-state index
was also tested by applying it in the 121 patients who
were evaluated for the second time ⬃3 months after
study enrollment, and by comparing the SSDAI scores
with those given by the investigators at the second
evaluation. The 2 scores were still closely correlated
(R ⫽ 0.817, P ⬍ 0.0001), and their differences were also
Figure 1. Correlation between the scores given by the investigators normally distributed (W ⫽ 0.933, P ⬍ 0.0001). Scores
and those calculated using the Sjögren’s Syndrome Disease Damage differed by 3 points, and were therefore outside the limit
Index (SSDDI), in 206 patients with primary SS. The correlation was
for 95% agreement (mean ⫾ SD difference 0.339 ⫾
statistically significant (R ⫽ 0.760, P ⬍ 0.0001). Data are presented as
box plots, where the boxes represent the 25th to 75th percentiles, the 1.29), in only 2.5% of the patients.
lines within the boxes represent the median, and whiskers represent The differences between the investigator scores
the 10th and 90th percentiles. The circle and the asterisk indicate an assigned at the first evaluation and the investigator
outlier and an extreme outlier, respectively. scores assigned at the second evaluation reflected a
clinically apparent variation in activity levels. Therefore,
the correlation between these differences and those
calculated from the scores obtained by applying the
SSDAI construction and validation. A multivar- SSDAI at the same observation times could be consid-
iate model with 11 variables was the best predictor of the ered indicative of the validity of this instrument as a
level of disease activity as judged and scored by the transition index. The variation in disease activity from
investigators. The variables included in this model, their the first evaluation to the second evaluation noted by the
␤ values, and their P values are shown in Table 3. Table investigators and the variation measured by the SSDAI
4 shows the items included in the SSDAI, with their
definitions and assigned scores. It is worth noting that
Table 3. Multiple linear regression model of disease activity in the
the variation in fatigue over time (change in fatigue in patients with Sjögren’s syndrome*
Table 3), which did not contribute significantly to the
Independent variable ␤ t P
multivariate model of disease activity, was included
among the items in the SSDAI (Table 4) since it Pleuropulmonary involvement 0.506 15.208 0.000
improved the overall validity of the index. Articular involvement 0.328 9.692 0.000
Change in vasculitis† 0.242 6.888 0.000
The scores obtained using the SSDAI were Lymph node/spleen enlargement 0.240 7.384 0.000
closely correlated with the scores assigned by the inves- Active renal involvement 0.187 5.737 0.000
tigators at the time of study enrollment (R ⫽ 0.872, P ⬍ Fever 0.183 5.528 0.000
Fatigue 0.176 3.793 0.000
0.0001) (Figure 2). The 2 scores did not differ or differed Change in salivary gland swelling 0.154 4.684 0.000
by 1 point in 77.2% of the patients, by 2 points in 19.9% Peripheral neuropathy 0.095 2.735 0.007
of the patients, and by 3 points in 2.9% of the patients. Leukopenia/lymphopenia 0.076 2.294 0.023
Change in fatigue† 0.059 1.630 0.105
These latter values were the only ones outside the limit
for 95% agreement (upper and lower limits set accord- * The dependent variable in this model was the numerical score for
disease activity (0–10) assigned by the investigator. This 11-item model
ing to a 2 SD difference [mean ⫾ SD 0.155 ⫾ 1.23]). The was a significant predictor of disease activity (R ⫽ 0.894, P ⬍ 0.0001).
differences between SSDAI scores and investigator † See Table 4 for explanation.
2228 VITALI ET AL

Table 4. Sjögren’s Syndrome Disease Activity Index*

Item Definition Score
Constitutional symptoms
Fever ⱖ38°C, not due to infections 1
Fatigue Sufficiently severe to affect normal activities 1
Change in fatigue New appearance or worsening of fatigue 1
Change in salivary gland swelling New appearance or increasing swelling of major salivary glands, not due to 3
infection or stones
Articular symptoms (any of the following) 2
Arthritis Inflammatory pain in ⱖ1 joint†
Evolving arthralgias New appearance or worsening of joint pain without signs of articular
inflammation†
Hematologic features
Leukopenia/lymphopenia ⬍3,500 mm3/⬍1,000 mm3 1
Lymph node/spleen enlargement Clinically palpable lymph node/spleen 2
Pleuropulmonary symptoms (any of the following) 4
Pleurisy Confirmed by imaging, not due to infection
Pneumonia (segmental or interstitial) Ground-glass appearance on computed tomography scan, not due to infection
Change in vasculitis New appearance or worsening or recurrent flares of palpable purpura 3
Active renal involvement (any of the following) 2
New or worsening proteinuria ⬎0.5 gm/day
Increasing serum creatinine level Above the normal limits
New or worsening nephritis Glomerular or interstitial, histologically defined
Peripheral neuropathy Recent onset (⬍6 months), confirmed by nerve conduction studies 1

* The index was constructed using variables selected by means of a multivariate linear regression model. The score value assigned to each item was
derived from the weight that the corresponding variable had in the model (␤ coefficient shown in Table 3). The definitions shown were provided
in the glossary included with the clinical chart in which patient data were recorded.
† Excluding other causes of joint/muscle pain, such as osteoarthritis or fibromyalgia.

were closely correlated (R ⫽ 0.683, P ⬍ 0.0001). The

differences between the change in investigator scores
from the first evaluation to the second evaluation and
the change in SSDAI scores were also normally distrib-
uted (W ⫽ 0.958, P ⬍ 0.001). Values were outside the
limit for 95% agreement (mean ⫾ SD ⫺0.24 ⫾ 1.68) in
only 6.6% of the patients.
Finally, the accuracy of the SSDAI in distinguish-
ing patients initially classified by the investigators as
having active or very active disease from those classified
as having inactive or mildly/moderately active disease
was assessed by ROC curve analysis. For this purpose,
an SSDAI score of ⱖ5 had high sensitivity (86.5%) and
specificity (87.6%).

Figure 2. Correlation between the scores given by the investigators at
the first observation time and those calculated using the Sjögren’s
Syndrome Disease Activity Index (SSDAI), in 206 patients with
primary SS. The correlation was statistically significant (R ⫽ 0.872,
P ⬍ 0.0001). Data are presented as box plots, where the boxes
represent the 25th to 75th percentiles, the lines within the boxes
represent the median, and whiskers represent the 10th and 90th
percentiles. Circles indicate outliers.
DISCUSSION
In this study levels of disease damage and disease
activity in patients with primary SS were evaluated. The
clinical and laboratory variables that were the best
predictors of disease damage or disease activity, as
globally assessed by the investigators, were used to
create 2 scoring systems, the SSDDI and the SSDAI.
The construct validity of each instrument was confirmed
by the correlation of index scores with the physician’s
global assessment of the respective disease state. Al-
though the correlation between the scores derived using
INDICES OF DISEASE DAMAGE AND DISEASE ACTIVITY IN SS
the constructed index and the investigator ratings was
certainly an expected result, the high value of the
correlation coefficients may be considered confirmation
of the validity of the SSDDI and the SSDAI.
Construct validity was also assessed by analysis of
the convergent validity and divergent validity of each
index. Even though activity and damage cannot be
considered completely independent since prolonged,
repeated, or uncontrolled phases of activity may cause
damage, the SSDDI and the SSDAI proved to be valid
instruments for measuring the 2 distinct domains. Fur-
thermore, validity of the SSDAI was also confirmed by
testing this instrument in a subgroup of patients with
active disease who underwent a second clinical evalua-
tion.
The responsiveness, or sensitivity to change, of
the SSDAI (i.e., its validity as a transition index) was
assessed by measuring its performance in accounting for
changes in disease activity over time in the subgroup of
patients with active disease. Finally, the SSDAI proved
to be highly efficient in identifying patients with active or
very active disease (those with a score of ⱖ5), who are
candidates for more aggressive therapy.
This is the first report to describe the develop-
ment of instruments to measure disease damage and
disease activity in SS. The creation of reliable tools to
measure these aspects of disease status has been consid-
ered a desirable goal by the scientific community and
believed to be particularly useful for future clinical trial
development (28). A modified version of the Systemic
Lupus International Collaborating Clinics/American
College of Rheumatology Damage Index (SDI) (13) has
been tested on a relatively small number of patients with
SLE and secondary SS, and is considered to be a rather
valid tool to measure some domains of disease damage
related to sicca symptoms (29). In contrast, no instru-
ments to assess disease activity in SS have yet been
proposed and validated.
Disease flares in SS are less easily detectable than
flares in SLE and RA, since the clinical course of SS is
usually more stable. However, the appearance of a
number of systemic features and laboratory parameters
usually characterizes the beginning of an active phase of
the disorder (30). As in other CTDs, in SS each disease
flare may lead to damage and failure of the involved
organ or system. Adequate treatment can allow control
of the acute phase of the disease and make the lesions
reversible, or limit tissue damage.
Since the concept of disease activity implies
reversibility, it is particularly important for an instru-
ment designed to measure the level of activity to be
sensitive to changes over time. To this end, the reversible
2229
findings included in the study protocol were scored
according to both their presence or absence and their
modification over time. Consequently, all of the items
selected for the SSDAI are considered to be reversible,
and most of these are simply defined on the basis of their
variation with respect to the previous observation time.
In contrast, assessment of disease damage requires a
reliable instrument to quantify the accumulated morbid-
ity due to irreversible lesions that may arise from
previous unresolved disease flares or from side effects of
medication. Finally, both disease damage and disease
activity are usually stratified according to the severity of
lesions. For instance, renal involvement or brain involve-
ment, which represent or may lead to severe outcomes,
obtain higher values when either activity or damage is
assessed.
The methodology used in the present study to
build the SSDDI and the SSDAI was the same as that
used by different international consensus groups to
develop and validate activity scales for SLE (8,31) and
SSc (12,32). This method is based on a multivariate
regression model in which the physician’s global assess-
ment is used as the dependent variable and considered
to be the external gold standard. The independent
variables, selected purely by means of statistical analysis,
are taken into account as potential items to be included
in the derived index, where stratification for severity can
be approximately quantified by the weight that each
variable assumes in the model.
The assumption that the physician’s global assess-
ment can represent the gold standard in assessing an
aspect of disease status, such as damage or activity, may
introduce some methodologic biases. Inaccuracies inher-
ent in the use of this method are well known, since
different physicians may judge a disease state differently,
given the influence of each physician’s experience and
cultural background (33,34). Selection of study investi-
gators with long and proven experience or training in the
specific field, and distribution to all of them of detailed
guidelines of the study protocol, as was done in the
present study, can drastically reduce this possible meth-
odologic defect. However, the use of standardized scor-
ing systems for different disease states or outcomes is
the only way to ensure avoidance of the variability
introduced by subjective judgment in this kind of clinical
evaluation.
The Delphi method, in which an expert commit-
tee arrives at a consensus on the variables potentially
predictive of a disease status, and the derived index is
tested for its construct validity in a group of true or
simulated patients, is an alternative way to obtain a
reliable tool for assessing aspects of disease status. This
2230
method was used in developing some widely accepted
indices for disease activity (SLE Disease Activity Index)
(4) and disease damage (SDI) (13) in SLE. Even in those
studies, however, validation of the indices and stratifica-
tion for severity were performed using the physician’s
global assessment as the external criterion. Comparison
studies assessing validity and sensitivity to change of
different scales for disease activity in SLE have shown
that the European Consensus Lupus Activity Measure
(ECLAM) (8), which was constructed by means of the
same methodology used in the present study, was at least
as valid and as sensitive as were other proposed indices
for measuring activity in both adult-onset and
childhood-onset SLE (31,33,35,36). For these reasons,
the ECLAM has been included among the recom-
mended outcome measures for this disorder (37,38).
The fact that the SSDDI and the SSDAI were not
developed in a multinational study may raise some
doubts about the content validity of these scales. The
wide spectrum of SS could not be completely covered by
the disease features observed in this cohort of patients
from a limited geographic area. Consequently, it is
possible that the derived indices fail to address some
rare clinical features that are potentially predictive of
disease activity or disease damage. This is likely, given
that multiple ethnic, genetic, and environmental factors
may influence the expression of SS (39–41). Additional,
larger studies, performed on a multinational basis, by
different investigators and in different cohorts of pa-
tients, are needed to assess the construct validity and
content validity of both the SSDDI and the SSDAI.
ACKNOWLEDGMENTS
We are grateful to Simon J. Bowman (University of
Birmingham, Birmingham, UK) for important contributions to
the study protocol preparation. We would like to thank Ms
Wendy Doherty for reviewing the English in the manuscript.
AUTHOR CONTRIBUTIONS
Dr. Vitali had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Vitali, Bombardieri, Del Papa, Gerli, Migliaresi, Mon-
tecucco, Tavoni, Valesini.
Acquisition of data. Baldini, Benucci, Covelli, De Vita, Epis, France-
schini, Gerli, Govoni, Maddali, Bongi, Maglione, Orefice, Priori.
Analysis and interpretation of data. Vitali, Palombi.
Manuscript preparation. Vitali.
Statistical analysis. Vitali, Palombi.
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