Clinimetric methods in Sjögren's syndrome

SJOGREN’S SYNDROME

Clinimetric methods in Sj¨ogren’s syndrome Gabriela Herna´ndez-Molina, MD, MS, and Tania Sa´nchez-Herna´ndez, MD

Objective: Clinimetric tools are useful in both clinical practice and research of Sj¨ogren’s syndrome. These instruments assist in the establishment of diagnosis and in the evaluation of disease status. We reviewed the available methods used to monitor sicca signs and symptoms, fatigue, quality of life as well as activity/chronicity in SS. Methods: PubMed and MEDLINE database were searched for the keywords “keratoconjunctivitis sicca diagnosis,” “dry eye and dry mouth assessment,” “sialometry,” “sialochemistry,” “Sj¨ogren’s syndrome outcomes,” “Sj¨ogren’s syndrome activity,” “Sj¨ogren’s syndrome damage,” “fatigue scales in Sj¨ogren’s syndrome,” and “Sj¨ogren’s syndrome quality of life.” All relevant articles and pertinent secondary references were reviewed. Results: As there is a moderate correlation between sicca symptoms and signs, the assessment of both is crucial. Most of the tests focus on oral and ocular dryness (vital dye staining, tear quantification, tear composition, sialometry, sialochemistry, etc.) and may not be disease specific. Symptoms such as dryness and fatigue have been evaluated with different instruments, being the PROFAD and ESSPRI disease-specific tools. Standardized measures for activity (SSDAI, SCAI, and ESSDAI) and chronicity (SSDDI and SSDI) indexes are currently used, however these methods still present limitations such as low external validity and cross-validation. Conclusion: The heterogeneous nature of the disease and its slow progression, challenge the evaluation of these patients. The use of composite measures might increase our ability to diagnose and evaluate disease activity and cumulative irreversible organ injury in this disease. However the distinction among oral and ocular activity vs. damage is still a matter of research. & 2013 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:627–639 Keywords: Sj¨ogren’s syndrome, Activity, Damage, Sicca symptoms, Clinimetry

P

rimary Sj¨ogren’s syndrome (SS) is an autoimmune disorder that primarily affects the exocrine glands, however extraglandular involvement is also common [1]. The natural history of disease is mainly characterized by the presentation of steady or slow progressing features, mainly sicca symptoms and fatigue. Although a subset of patients may experience flares secondary to extraglandular activity [2]. In addition, evaluation of subjective symptoms along with objective measurements is necessary due to the moderate correlation of sicca symptoms and signs [3]. The heterogeneous nature of the disease further challenges this evaluation. Certain clinimetric methods assist diagnosis of SS and recently the development of validated criteria for the assessment of the activity and accrual damage is a matter of

Immunology and Rheumatology Department, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Mexico City, Mexico. Address reprint requests to Gabriela Herna´ndez-Molina, MD, MS, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Vasco de Quiroga 15, Col. Seccio´n XVI 14000, Me´xico City, Me´xico. E-mail: [email protected].

0049-0172/12/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2012.09.008

research. This review focuses on available methods used to evaluate sicca symptoms, fatigue and quality of life, as well as clinimetric tools to evaluate disease activity and diseaserelated damage.

METHODS PubMed and MEDLINE databases were searched from date of inception until April 2012 for the keywords “keratoconjunctivitis sicca diagnosis,” “dry eye and dye mouth assessment,” “sialometry,” “sialochemistry,” “Sj¨ogren’s syndrome outcomes,” “Sj¨ogren’s syndrome activity,” “Sj¨ogren’s syndrome damage,” ”fatigue scales in Sj¨ogren’s syndrome,” and “Sj¨ogren’s syndrome quality of life.” The search was limited to reports in human subjects and in English language. Relevant articles and pertinent secondary references were retrieved. We critically analyzed all published materials with emphasis on manuscripts presenting original data regarding the evaluation of signs and symptoms of SS. 627

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Clinimetric methods in Sj¨ogren’s syndrome

Figure 1 Flow chart and selection process of the included publications.

RESULTS The process of literature search and selection is depicted in Figure 1. The database search identified 564 articles that were screened for eligibility. Four hundred and sixty articles were excluded on the basis of abstract evaluation because they were irrelevant to study subject (either not related to SS or not describing clinimetic modalities). The remaining potentially relevant 104 articles were retrieved for detailed full text evaluation. We also searched by hand relevant secondary references and this resulted in 48 references. After these abstracts were evaluated, 15 publications were also selected to be read as full text. Fifty-five out of 119 potentially relevant full-text articles, identified by the electronic and manual search, were excluded due to not containing sufficient and clear information or being review articles. Therefore, 64 studies were selected for the present review. Objective tests for dry eyes and dry mouth Ocular The aim of the ocular tests (Table 1) is to assess the integrity of the ocular surface, the volume and quality of tear film [4]. The ocular surface is evaluated with vital

dyes such as Rose Bengal (RB), fluorescein and lissamine green [4]. Fluorescein dye reveals corneal changes by the location and pattern of its staining and also provides the basis for measuring the tear break-up time [5]. RB and lissamine green dyes discover denuded epithelium lesions and queratinized cells that are characteristic of keratoconjunctivitis sicca (KCS) [6,7]. However the use of lissamine green is preferred since RB may cause ocular irritation and pain [7]. Some semi-quantitative methods to assess the severity of KCS using vital dye staining have been proposed [8,9]. For instance, after staining with RB or any other ocular dye, the Van Bijsterveld scale divides the ocular surface into three zones: nasal bulbar conjunctiva, cornea, and temporal bulbar conjunctiva. The intensity of staining is scored up to 3 points at each section (1 ¼ sparsely scattered, 2 ¼ densely scattered, and 3 ¼ confluent). KCS is diagnosed with a score Z4 [8]. Recently the Sj¨ogren’s International Collaborative Clinical Alliance (SICCA) proposed the Ocular Staining Score (OSS). This index is the sum of 0–6 points for fluorescein corneal staining and 0–3 points for lissamine green staining at both nasal and temporal bulbar conjunctivae. KCS is diagnosed with a score Z3 [9]. Overall vital dyes are well accepted methods for the evaluation of KCS, however corneal epithelial staining is a dynamic and

Test

Basis and Method

Abnormal Value

Diagnostic Performance

Comment

Refs.

Schirmer test

Semi-quantitative measurement of tear secretion made by tear test strips Schirmer-I (without topical anesthetic): stimulation of both minor and major lacrimal glands. Jones test: same as Schirmer-I but with topical anesthetic. Schirmer-II: evaluates maximal lacrimal gland output by means of introducing a cotton tipped swab into the nose and mechanically stimulating the nasolacrimal gland reflex. Index of tear film stability. A 1% fluorescein solution is instilled in the inferior fornix of both eyes. After blinking, the interval in seconds between the last blink and the first break on tear film is measured Index of corneal and conjunctival surface integrity

r5 mm/5 min

Se 4276% Sp 7276% Se 60% Sp 88%

Screening and clinical practice test.

[5,11]

r10 s

Se 9282% Sp 1786%

Clinical practice test. Slit-lamp needed. Age and technique dependent.

[4,11]

Bijsterveld score Z4 Ocular staining score Z3

Se 64%

Clinical practice test. Slit-lamp needed.

[4–6,8,9]

Break-up time

Vital stains

Tear function index (TFI)

Tear meniscus

Evaluates tear production and drainage. After instilling 10 mL of fluorescein into the conjunctival fornix, the Schirmer-I test is performed. The colored filter strip is then compared with known standards to determinate tear clearance rate (TCR). Then the TFI is obtained by dividing the Schirmers value by the TCR Measurement of basal tear volume between the ocular surface and the lower lid margin

o96

o0.3 ⫾ 0.1 mm

Sp 81.7% Se 89% Sp 37% Se 78% Sp 91%

NA

Easy to perform Age dependent

Clinical practice test. Technique dependent.

[14]

Research test. Video meniscometer and slit-lamp needed.

[22]

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez

Table 1 Ocular Tests

629

630

Table 1 (continued ) Test

Basis and Method

Abnormal Value

Diagnostic Performance

Comment

Refs.

Tear osmolarity

Osmolarity is increased as a result of cytokines liberation. Decreased tear protein levels represent glandular dysfunction.

Z316 mOsm/L

Se 5994% Sp 9497% Se 25%

Research test. Osmometer needed.

[19,20]

Research test. Laboratory methods needed. Age dependent.

[8,16–18]

Tear proteins

Lysozyme o1– 3 mg/mL Lactoferrin o2 ⫾ 1.1 mg/ml.

Sp 96% Se 2878% Sp 6790%

Ferning test

Brush cytology

Cornea aesthesiometry

Evaluation of corneal sensitivity in five corneal points

Se: senstitivity; Sp: specificity.

4Grade II/III

Se 7490% Sp 10%

Research test. Light microscopy needed. Age dependent

[15,25]

Score 46

NA

Research test. Light microscopy needed. Age dependent

[24]

Score Z2

Se 94%

[24]

Sp 10%

Research test. Light microscopy needed. Age dependent

Se 80% Sp 67%

Research test. Aesthesiometer needed

40.57 g/mm2

[23]

Clinimetric methods in Sj¨ogren’s syndrome

Imprint cytology

An index of tear film stability. Crystallization of a fresh tear without staining is visualized under the microscope, and classified according to its patterns: Grade I: uniform arborization Grade II: shorter and thicker ferns Grade III: smaller ferns and incompletely formed Grade IV: absence of ferning phenomenon Evaluation of type and grade of inflammation by collecting conjunctival epithelial cells under local anesthesia using cellulose filters. Score 020 Squamous metaplasia. Grade 05

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez

time-sensitive process, therefore late staining artifacts may be present. In addition these methods present some degree of subjectivity [9]. A clinical test to assess the stability of the tear film is the break-up time. This is defined after the application of fluorescein dye, as the time in seconds for a dry spot to appear on the corneal surface after a complete blink [10]. Although being a widely used method, it depends on the concentration of fluorescein, the number of blinks and the patient’s age [5]. On the other hand, tear volume is assessed generally by the Schirmer-I test [11]. Furthermore there are several combinations or modifications of this test in the attempt to improve the detection of ocular dryness, for example the Jones test [12], the combination of Schirmer-I and phenol red thread [13] and the tear flow index [14]. Unfortunately all tear volume tests are affected by patient’s age [15]. As a gradual destruction of the lacrimal gland leads to diminished levels of tear proteins (lysozyme, lactoferrin, and tear specific prealbumin), some authors have proposed the measurement of these proteins for the identification of dry eyes [8,16–18]. However, the most frequent cause of diminished tear gland protein production is also related to age involution [8]. Other tests such as tear film osmolarity [19,20], tear evaporation [21], tear meniscus [22], cornea aesthesiometry [23], ocular surface impression cytology [24], and crystallization [15,26] have also been described. Although all these methods provide different qualitative information, they have not achieved general clinical acceptance due to reduced accessibility, low specificity, and lack of validation. Finally the Schirmer-I test and ocular surface vital dye staining have been incorporated to different sets of SS classification criteria [27,28]. For instance according to the 2002 AECG criteria, the Schirmer-I test and the RB (or other ocular dye) score are part of the objective assessment of dry eye [27]. Conversely the current ACR classification SS criteria only considers the ocular staining score [28]. Further none of these methods are a part of the activity assessment, whereas the Schirmer-I test is a part of both chronicity indexes [29]. Oral Traditionally the salivary gland function can be evaluated by sialometry (salivary flow rate measurements) and by sialochemistry methods that analyze the saliva composition (Table 2) [30,31]. Other methods such as impression cytology of the bucal mucosa [24,25], salivary electrophoresis [32], saliva ferning [24,25,33], and the use of iodine–starch reaction to identify the number of lip salivary gland ostia [34] have also been described. Sialometric methods are easy to perform and provide objective measurements. However normal values decrease with age, fluctuate throughout the day (highest in the late afternoon) and may be modified by hydration, body position, smoking, exposure to light and drugs [35].

631

Sialometry methods include the wafer test [36], the Saxon test [37], the oral Schirmer test [38], the candy weight loss test [39], the palatal [40], and parotid glands saliva flow [41], the capsaicin-stimulated salivary flow using filter paper [42] and more traditionally the whole saliva collection, with or without stimulus [15,43]. The whole non-stimulated salivary flow (NSWSF) reflects the basal flow of all the salivary glands [43,44]. NSWSF is a part of the AECG classification criteria [27], contrary to the ACR criteria which does not include it [28]. Interestingly the stimulated whole salivary flow has been recently proposed as a noninvasive surrogate biomarker of inflammation and fibrosis in salivary minor glands [45]. None of the sialometric methods mentioned above participate in the assessment of disease activity. In regard to organ damage, NSWSF is present in both accrual damage indexes [2,29]. Finally, sialochemistry is used on the basis that electrolyte or protein saliva composition may be altered by the disease [30]. An advantage over sialometry is that it has the potential to show alterations during incipient disease. However this method is hampered by the lack of salivary reference values and specialized laboratory equipment [30]. Symptoms scores Ocular and oral dryness Non-specific instruments. For the evaluation of dry eye in SS, some non-specific disease validated questionnaires such as the Ocular surface disease index (OSDI) [46] and the Dry Eye Questionnaire (DEQ) have been used [47]. The OSDI includes 12 questions about ocular discomfort, vision-related function and environmental triggers in the previous week [43]. The DEQ and shorter versions such as the DEQ-5 characterize the frequency of ocular surface symptoms and their diurnal intensity [44]. In the same vein, the xerostomia inventory (XI) evaluates oral dryness based on 11 items scored in a single scale, however it was constructed in older individuals without primary SS [48].

The Sicca symptoms inventory (SSI) was the first disease-specific score designed to evaluate ocular, oral, vaginal, and skin dryness in primary SS patients over a period of 2 weeks [49]. The index incorporated a questionnaire derived from patient interviews and published sicca symptom questions. The severity of each domain is scored by a 0–7 Likert scale, with an overall maximal score of 28. The ocular domain evaluates three facets: sore eyes, eye irritation, and poor vision. The oral domain is divided in five facets: difficult eating, dry throat, bad breath, wetting mouth, and oral problems. Vaginal and skin dryness are other individual domains which are evaluated. However the sensitivity to change of this questionnaire still remains to be determined. The SSI is also part of the PROFAD-SSI [50] score, which additionally includes an assessment of fatigue (see below) and other symptoms (Table 2).

Disease-specific instruments.

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Clinimetric methods in Sj¨ogren’s syndrome

Table 2 Oral Tests Test Whole saliva flow collection

Palatal saliva flow

Stimulated parotid saliva flow Wafer test

Saxon test

Oral Shirmer test

Candy weight loss test

Impression cytology

Iodine–starch reaction

Basis and Method

 Non-stimulated: saliva collection is performed during 5 min or 15 min by the spitting method.  Stimulated: after chewing wax or gum for 1 min, the volume of saliva expectorated during that time is measured. Dry weighed 8 mm disks are placed on both sites of the palate, at the level of the upper first molars. Collection is carried out for 30 s and then the disk is weighted. Saliva is collected under a stimulus with a cannula or other collection device. After swallowing any residual saliva, the wafer is put on the center of the subject’s tongue, and wafer dissolution time is measured. Saliva production is quantified by weighing a gauze before and after chewing it for 2 min. After placing a filter paper on the floor of the mouth, the wetted length after 5 min is measured. The weight loss of a standard hard sugar candy after 3 min of passive incubation between tongue dorsum and palate is tested. Cellulose acetate paper is applied on the internal surface of the inferior lip and the obtained sample is stained with hematoxylin and PAS. A test tape of 1  1 cm2 containing iodine and starch is set

Abnormal Test Non-stimulated r1.5 ml/15 min Stimulated r0.6 ml in 1 min

Diagnostic Performance

Disadvantage

Refs.

Se 5664% Sp 81%

Clinical practice test. Affected by age, time of the day and drugs

[15,43]

Se 66% Sp 56%

1.35 ⫾ 2.5 mcm2 min1

NA

Clinical practice test. Affected by age, time of the day and drugs

[40]

1.5 ml/5 min

NA

Clinical practice test. Special collection material needed

[41]

44 min

In combination with Schirmer-I Se 77% Sp 82%

Screening/clinical practice test Affected by age, time of the day and drugs

[36]

o2.75 g in 2 min

NA

[37]

r30 mm/5 min

Se 67.9% Sp 62.8%

o0.23 g

Se 92% Sp 85%

Screening/clinical practice test Affected by age, time of the day and drugs Screening/clinical practice test Affected by age, time of the day and drugs Screening/clinical practice test Affected by age, time of the day and drugs

Keratinized epithelium is abnormal

NA

Research test. Light microscopy needed Age dependent

[24,25]

Controls 9.4 ⫾ 2.5 spots

NA

Screening/clinical practice test Age dependent

[34]

[38]

[39]

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez

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Table 2 (Continued ) Test

Capsaicinstimulated salivary flow

Sialochemistry

Basis and Method on the labial mucosa anteriorly to the labial frenulum for 30 s. The number of blue spots corresponds to the number of salivary gland ostia. An assay system comprising 5 spots containing starch, potassium iodide and a coloring reagent with or without capsaicin is placed at the mouth.

Measurement of specific proteins (lactoferrin and lysozyme), carbohydrate, and electrolytes.

Abnormal Test

Diagnostic Performance

Disadvantage

Refs.

Oral dryness 4.5 ⫾ 3.1 spots Sj¨ogren’s 2.1 ⫾ 1.3 spots

In controls the capsaicinstimulated salivary flow increased from 1.2 ⫾ 1.4 to 2.9 ⫾ 1.3 colored spots No change in the hyposalivation group Laboratory kits Cut-offs

NA

Screening/clinical practice test

[42]

Age dependent

Lactoferrin Se 58% Sp 75% Lysozyme Se 3% Sp 100%

Research test No agreement about significant cut-offs. Variation between resting and stimulated saliva. Moderate amount of saliva is required

[30]

Se: senstitivity; Sp: specificity

Similarly, two questions regarding oral and ocular symptoms are part of the 2002 AECG classification SS criteria [15], yielding a sensitivity of 81.4 and 84.9% respectively and a specificity higher than 80% [51]. Furthermore retesting these questions a year after, their reliability was of 96.4 and 98.2%, respectively [52]. Conversely current ACR classification criteria do not incorporate symptomatic manifestations, in the attempt to avoid misclassification of asymptomatic patients [28]. Finally in order to have a disease-specific and a simple symptoms index, the EULAR Sj¨ogren’s syndrome patient reported index (ESSPRI) was recently developed. It is a very simple patient-reported index designed to measure the three main symptoms of patients with primary SS: dryness, joint or muscular limb pain, and fatigue (mental or somatic). Each component of the ESSPRI is measured with a single 0–10 numerical scale, followed by calculation of the mean of the three scales. This index highly correlates with the corresponding PROFAD and SSI domains as well as with the patients global assessment [53]. However this instrument still lacks external validation and cross-validation studies of the ESSPRI and PROFAD-SSI are needed. Fatigue Fatigue is a common symptom in SS, to the extent that it is considered in the SSDAI [2] and SCAI [54] activity

indexes. A number of fatigue measurement instruments have been used for its assessment. Some of them are uni-dimensional whereas others include several domains evaluating different aspects of fatigue (mental vs. physical items). The visual analog scales (VAS) and the Medical Outcomes Study Short-Form (SF-36) [55] are the most frequently used instruments. Other tools such as the Functional Assessment of Chronic Illness Therapy (FACIT) scale [56], the Chalder fatigue scale [57], the Multidimensional Fatigue Instrument (MFI) [58], the Fatigue Severity Scale (FSS) [59], and the Fatigue Impact scale [60] have also been reported in SS studies [61,62]. Bowman et al. proposed the Profile of fatigue and discomfort (PROFAD-SSI) scale as a specific 64 questionnaire instrument for primary SS patients (Table 3). This tool evaluated eight domains (somatic fatigue, mental fatigue, arthralgia, vascular dysfunction, oral, ocular dryness, cutaneous, and vaginal dryness) scored on a Likert scale [50]. The somatic and mental fatigue domain scores can be summated to form the Profile of Fatigue (PROF) score. Fatigue, arthralgias and vascular dysfunction domains form the PROFAD score whereas the sicca domains provide the SSI score [50]. Regarding the individual domains of physical and mental fatigue, these domains can vary independently and only the

634

Clinimetric methods in Sj¨ogren’s syndrome

Table 3 Symptoms and Quality of Life Assessment Feature Ocular symptoms Oral symptoms Fatigue

Instrument

 Ocular surface disease index (OSDI)  Dry eye question (DEQ) Xerostomia inventory (XI)

 Visual analog scale (VAS)  Medical outcomes study shortform (SF-36)

 Functional assessment of chronic illness therapy (FACIT)

 Chalder fatigue scale  Multidimensional fatigue instrument (MFI)

 Fatigue severity scale (FSS)  Fatigue impact scale Sicca and other symptoms

Profile of fatigue and discomfort (PROFAD-SSI)

EULAR Sj¨ogren’s syndrome patient reported index (ESSPRI) Quality of life

 Medical outcomes study short    

form (SF-36) World health organization quality of life questionnaire (WHOOQOL-BREF) EuroQol 5-domain (EQ-5D) Oral health impact profile (OHIP49) National eye institute visual function questionnaire (NEIVFQ) Impact of dry eye on everyday life questionnaire (IDDEL)

Domains Ocular discomfort, vision related function and environmental triggers. Frequency and diurnal intensity Unidimensional

Unidimensional General health, physical functioning role functioning physical, bodily pain, social functioning, role functioning emotional, mental health and vitality Unidimensional Somatic and mental fatigue General fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue Unidimensional Cognitive, physical and psychosocial functioning Profile of fatigue (PROF) Fatigue Sicca symptoms inventory (SSI) Oral Ocular Skin Vaginal PROFAD Fatigue Arthralgia Vascular dysfunction Dryness Muscular pain Fatigue See above Physical, psychological, social relationship and environment. Mobility, self-care, usual activities, pain/discomfort, anxiety/ depression and global health status. Functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability and handicap. Visual symptoms, vision specific social functioning, mental health, role functioning and dependency. Dry eye symptom-bother, dry eye impact on daily life and dry eye treatment satisfaction.

physical domain correlates with the VAS fatigue scale. Later the same authors validated a short version (19questions) of the PROFAD-SSI [63]. Finally as previously mentioned, the assessment of fatigue is also part of the recent published ESSPRI [53]. Quality of life Quality of life (QoL) is an important concept in primary SS. Generic and some organ specific measures have been designed to aid in the evaluation of general well-being of the patient. The generic measurements include the SF-36 [55], the World Health Organization Quality of Life questionnaire (WHOOQOL-BREF) [64], and the EuroQol 5-domain (EQ-5D) [65].

Refs. [46] [47] [48] [55] [56] [57] [58] [59] [60]

[49]

[50]

[53] [55] [64] [65] [66]

[67] [68]

Oral/ocular specific measures can be used to evaluate ocular or oral health-related QoL aspects as well as social functioning and general health items [66,67]. For instance the Oral Health Impact Profile (OHIP49) is a scale index of the social impact resulting from oral disorders that comprises of seven domains: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap [66]. In the same manner, the National Eye Institute Visual Function Questionnaire (NEI-VFQ) includes vision-related quality of life domains such as vision-specific social function, dependency, and mental status [67]. The impact of dry eye on Everyday Life questionnaire (IDDEL) assesses dry eye impact in 3 modules: symptom-bother, daily activities,

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez

emotional impact, and impact on work [68]. Even though these instruments are oral/ocular specific and seem to discriminate between severity levels of QoL impairment [69], none were specifically designed for SS patients. Disease status The concept of disease status encompasses measurements of disease activity and organ damage [70]. For instance Asmussen et al. proposed a quantitative assessment of clinical disease that included glandular, extraglandular and laboratory (hemoglobin, platelets, and white cell count) items, however measures of disease activity and organ damage were combined [71]. Theoretically disease activity is reversible whereas damage is not, therefore there is a need for validated indexes that evaluate each concept. Activity Instruments that measure disease activity in primary SS are important in both clinical practice and in treatment trials. Today’s available instruments (Table 4) are similar to those used in the assessment of Systemic Lupus Erythematosus (SLE) [72,73]. For instance the SS Disease Activity Index (SSDAI) [2] is similar to the European Consensus Lupus Activity Measurement (ECLAM) [72]. The SSDAI is a global index (with maximal score of 21) that evaluates constitutional and articular symptoms, hematologic features, pleuropulmonary symptoms, vasculitis, renal involvement, and peripheral neuropathy. A cut-off Z5 is accurate to distinguish patients with more active disease [2]. Moreover, the Sj¨ogren’s Syndrome Clinical Activity Index (SCAI) [54] follows the principle (severity is scored according to the “intention to treat”) of the BILAG activity SLE index [72]. The SCAI is a composite score of nine domains (fatigue, constitutional, musculoskeletal, skin, respiratory, neurological, renal, salivary gland, and hematological), that are first evaluated as absent (0 points), improving (1 point), the same (2 points), worse (3 points) or new (4 points) in comparison with a prior 4 week visit. Then this first scoring is used to score each domain with an intention to treat alphabetical score (AE) according to established definitions. Finally the alphabetical score is again converted into a numeric variable (A ¼ 9, B ¼ 3, C ¼ 1 and D/E ¼ 0), being the maximal score ¼ 81 points [54]. Recently the EULAR Sj¨ogrens syndrome disease activity index (ESSDAI) addressed the global activity of the systemic features of the disease. The Delphi methodology was followed to design this index of 12 domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonar, renal, muscular, peripheral nervous system, central nervous system, hematological, and biological) [29]. The biological domain includes serological markers of B-cell activation. The sensitivity to change this index was first evaluated retrospectively [74] and recently

635

prospectively in a group of patients receiving rituximab [75]. In both the studies, the index accurately detected changes in activity and disease stability over the time. When comparing the three available activity indexes, the ESSDAI showed a better correlation with physician global assessment scale (PhGA) and detected changes more accurately than the SSDAI and SCAI [75]. Studies addressing the cross-validation of these instruments are warranted. Chronicity There are two approaches that evaluate cumulative permanent damage in primary SS: the Sj¨ogren’s Syndrome Damage Index (SSDI) [76] and the SS Disease Damage Index (SSDDI) [2] (Table 4). Both indexes were developed in single national cohort and include ocular, oral and systemic domains. An advantage of the SSDI is that it recognizes cardiovascular, gastrointestinal and musculoskeletal items, methodology based on the SLE damage index (SLICC/AR) [77]. The SSDI comprises the following domains (maximal score ¼ 27): ocular, oral, neurological, renal, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, endocrine, and malignancy. On the other hand, the SSDDI methodology was based on expert validation and involves the following domains (maximum score ¼ 16): oral, ocular, neurologic, pleuropulmonar, renal, and lymphoproliferative. DISCUSSION Various methods have been employed to assess the salivary and lacrimal involvement in SS, however a limited number of them have been subjected to evaluation to establish their clinical utility. In addition as there is a lack of a gold standard diagnostic test, combinations of different tests are commonly performed to help determining an accurate diagnosis. Some tools seem to be more appropriate for screening purposes (i.e. Schirmer test and wafer test) whereas others have a higher diagnostic value (i.e. vital dies and sialometry) or are employed only in research (i.e. sialochemistry, ferning test, corneal aesthesiometry, etc). For instance in regards to the ocular component, KCS is undoubtedly a key feature. The application of ocular surface staining has been used for many years and new and more reliable staining methods are in current research. For the oral component, the NSWSF seems to be a reliable method. This method is part of the AECG criteria [27], and even though the current ACR criteria [28] did not include it as an item, NSWSF is recognized as a suitable alternative for diagnostic purposes. In addition it is important to have validated symptom questionnaires, since a fundamental mainstay in clinical medicine and SS is the patient’s ability to identify change in their symptoms. Further the development of new biologic agents increases the need of reliable clinimetric tools. These instruments should aid first in the establishment of an

636

Clinimetric methods in Sj¨ogren’s syndrome

Table 4 Activity and Damage Indexes Index Activity EULAR Sj¨ogrens syndrome disease activity index (ESSDAI)

Sj¨ogren’s syndrome disease activity index (SSDAI)

Sj¨ogren’s syndrome clinical activity index (SCAI)

Damage SS disease damage index (SSDDI)

Domains

Maximal Score per Item

Refs.

Constitutional (fever and weight loss) Lymphadenopathy Glandular Articular (arthralgias or synovitis) Cutaneous (erythema multiform and vasculitis) Pulmonary (interstitial lung disease) Renal (proteinuria and renal failure) Muscular (myositis) Peripheral nervous system Central nervous system Hematological (neutropenia, anemia and lymphopenia) Biological (hypocomplementenemia cryoglobulinemia, hypergammaglobulinemia or high IgG levels) Constitutional – Fever – Fatigue – Change in fatigue – Change in salivary gland swelling, Articular – Arthritis or evolving arthralgia Hematologic – Leukopenia/lymphopenia – Lymph/spleen enlargement Pleuropulmonar – Pleurisy or segmental or interstitial pneumonia Change in vasculitis Active renal involvement – New or worsening proteinuria or increasing serum creatinine level or new or worsening nephritis Peripheral neuropathy – Fatigue – Constitutional (fever, swollen lymph glands/spleen, weight loss). – Musculoskeletal (arthralgias, morning stiffness, arthritis, myalgia, weakness and myositis). – Skin/vasculitis (Raynaud, vasculitis and SCLE). – Respiratory (shortness of breath, pleural-pericardial pain, pleural effusion and interstitial lung disease). – Neurological (peripheral and cranial neuropathy, central nervous system). – Renal (dipstick proteinuria, 24 h proteinuria, active urinary sediment, active nephritis, nephrotic syndrome, serum creatinine, creatinine clearance and blood pressure). – Salivary gland – Hematological (Hemoglobin, total white cell count, neutrophils, lymphocytes,platelets, evidence of active hemolysis, Coombss test, ESR and CRP). – Immunology (ANA, dcDNA, C3, C4, IgG, IgA, IgM, Anti-Ro, anti-La, cryoglobulins and paraprotein). – Ocular test (Schirmer -1 test) – Salivary test (unstimulated salivary flow rate)

2 3 2 3 3 3 3 3 3 3 3 2

[29]

Oral/salivary damage – Salivary flow impairment – Loss of teeth Ocular damage

[2] 1 1 1 3 2 1 2 4 3 2 1

9 9 9 9 9 9 9 9 9 Non additional score is provided

[54]

[2] 1 1

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez

637

Table 4 (Continued ) Index

Domains – Tear flow impairment – Structural abnormalities

Sj¨ogren’s syndrome damage index (SSDI)

Neurological damage – CNS involvement – Peripheral neuropathy Pleuropulmonar (pleural fibrosis, interstitial fibrosis and significant irreversible functional damage) Renal impairment (increased serum creatinine level or reduced glomerular filtration rate, tubular acidosis and nephrocalcinosis) Lymphoproliferative disease (B-cell lymphoma, multiple myeloma and Waldenstr¨om macroglobulinemia) – Ocular (corneal scarring, abnormal Schirmer-I result, tear duct surgery, cataract, retinal change and chronic blepharitis), – Oral domain (caries and teeth loss), salivary gland swelling, unstimulated salivary flow 0 ml/15 min, oral infection, parotid surgery, gum disease, oral ulceration and dysphonia). – Neurological (cranial, peripheral, mononeuritis, cognitive impairment and other central nervous system). – Renal (nephrocalcinosis, renal tubular acidosis, glomerular filtration rate o50%, proteinuria 43.5 g, end stage renal disease and chronic cystitis). – Pulmonary (pleural fibrosis, pulmonary fibrosis, pulmonary hypertension and pulmonary infarction). – Cardiovascular (cardiomyopathy, hypertension, ischemic heart disease, heart valve disease, pericarditis and myocardial infarction). – Gastrointestinal (chronic pancreatitis, celiac disease, primary biliary cirrhosis, chronic sclerosing cholangitis, chronic autoimmune hepatitis and upper GI surgery). – Musculoskeletal (erosive arthropathy, osteoarthritis, osteoporosis, avascular necrosis and skin ulcers). – Endocrine (hypothyroidism, pernicious anemia, hyperthyroidism and diabetes). – Malignancy (paraproteinemia, other malignancy, macroglobulinemia, cryoglobulinemia and lymphoma).

accurate diagnosis and secondly in the follow-up of disease behavior. In SS, this assessment is challenging due to high prevalence of subjective symptoms and a relative stable course of disease (flares are less easily detectable). Nowadays, valid and reliable instruments for measuring disease activity and chronicity exist; however they still present certain limitations such as low external validity, design based on patients with mild disease activity, lack of cross-validation and most challenging, reduced distinction between acute and chronic injury in the oral and ocular domain. In conclusion, it seems that clinimetric methods are essential for SS and that further studies using better composite measures should increase our ability to diagnose and accurately evaluate activity or cumulative irreversible organ injury in this disease.

Maximal Score per Item

Refs.

1 1 2 1 2 2 5

1 1 1 1 1 1 1 1 1 1

[76]

REFERENCES [1] Ramos-Casals M, Font J. Primary Sj¨ogren’s syndrome: current and emergent aetiopathogenic concepts. Rheumatology 2005;44:1354-67. [2] Vitali C, Palombi G, Baldini C, Benucci M, Bombardiere S, Covelli M, et al. Sj¨ogren’s syndrome disease damage index and disease activity index. Scoring systems for the assessment of disease damage and disease activity in Sj¨ogren’s syndrome derived from an analysis of a cohort of Italian patients. Arthritis Rheum 2007;56:2223-31. [3] Hay E, Thomas E, Pal B, Hajeer A, Chambers H, Silman A. Weak association between subjective symptoms of and objective testing for dry eyes and dry mouth: results from a population based study. Ann Rheum Dis 1998;57:20-4. [4] Versura P, Frigato M, Mule´ R, Malavolta N, Campos E. A proposal of new ocular items in Sj¨ogren’s syndrome classification criteria. Clin Exp Rheumatol 2006;24:567-72.

638 [5] van Bijsterveld O. Diagnosis and differential diagnosis of keratoconjunctivitis sicca associated with tear gland degeneration. Clin Exp Rheumatol 1990;8:S3-S6. [6] Norn M. Vital staining of the cornea and conjunctiva. Am J Ophthalmol 1967;64:1078-80. [7] Machado LM, Castro RS, Fontes BM. Staining patterns in dry eye syndrome: rose bengal versus lissamine green. Cornea 2009;28:732. [8] van Bijsterveld O. Diagnostic test in the sicca syndrome. Arch Ophthalmol 1969;82:10-4. [9] Whitcher J, Shiboski C, Shiboski S, Heidenreich A, Kitagawa K, Zhang S, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sj¨ogren’s syndrome international registry. Am J Ophthalmol 2010; 149:405-15. [10] Mengher L, Pander K, Bron A. Non-invasive tear film break-up time: sensitivity and specificity. Acta Ophthalmol 1986;64: 441-4. [11] Kalk W, Mansour K, Vissink A, Spijkervet F, Bootsma H, Kalenberg C, et al. Oral and ocular manifestations in Sj¨ogren’s syndrome. J Rheumatol 2002;29:924-30. [12] Jones L. The lacrimal secretory system and its treatment. Am J Ophthalmol 1966;51:58-66; Jones L. The lacrimal secretory system and its treatment. Am J Ophthalmol 1966;62:47-60. [13] De Monchy I, Gendron G, Miceli C, Pogorzalek N, Mariette X, Labetoulle M. Combination of the Schirmer I and phenol red thread tests as a rescue strategy for diagnosis of ocular dryness associates with Sj¨ogren’s syndrome. Invest Ophthalmol Vis Sci 2011;52:5167-73. [14] Xu KP, Yagi Y, Toda I. Tear function index. Arch Ophthalmol 1995;113:84-8. [15] Vitali C, Moutsopoulos H, Bombardieri S, The European Community Study Group on Diagnostic Criteria for Sj¨ogren’s syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sj¨ogren’s syndrome. Ann Rheum Dis 1994;53: 637-47. [16] Da Dait S, Moncada A, Priori R, Valesini G, Pivetti-Pezzi P. The lactoferrin tear test in the diagnosis of Sj¨ogren’s syndrome. Eur J Ophthalmol 1996;6:284-5. [17] Goren M, Goren S. Diagnostic test in patients with symptoms of keratoconjunctivitis sicca. Am J Ophthalmol 1988;106:570-4. [18] Lucca J, Nun˜ez J, Farris F. A comparison of diagnostic tests for keratoconjunctivitis sicca: lactoplate, Schirmer, and tear osmolarity. Contact Lens Assoc Ophthamol J 1990;16: 109-12. [19] Utine CA, Bıc- akc- ıgil M, Yavuz S, C - iftc- i F. Tear osmolarity measurements in dry eye related to primary Sj¨ogrens syndrome. Curr Eye Res 2011;36:683-90. [20] Tomlinson A, Khanal S, Ramaesh K, Diaper D, McFadyen A. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006;47:4309-15. [21] Roland M, Refojo M, Kenyon K. Increased tear evaporation in eyes with keratoconjunctivitis sicca. Arch Ophthalmol 1983;101:557-8. [22] Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the diagnosis of dry eye. Curr Eye Res 1996;15:653-61. [23] Versura P, Frigato M, Cellini M, Mule R, Malavolta N, Campos E. Diagnostic performance of tear function tests in Sj¨ogren’s syndrome patients. Eye 2007;21:229-37. [24] Aguilar A, Fonseca L, Craxatto O. Sj¨ogren’s syndrome: a comparative study of impression cytology of the conjunctiva and bucal mucosa, and salivary gland biopsy. Cornea 1991;10: 203-6. [25] Maragou M, Vaikousis E, Ntre A, Koronis N, Georgiou P, Hatzidimitriou E, et al. Tear and saliva ferning test in Sj¨ogren’s syndrome. Clin Rheumatol 1996;15:125-32.

Clinimetric methods in Sj¨ogren’s syndrome [26] Vaikoussis E, Georgiou P, Nomicarios D. Tear mucus ferning in patients with Sj¨ogren’s syndrome. Doc Ophthamol 1994;87: 145-51. [27] Vitali C, Bombardiere S, Jonsson R, Moutsopoulos H, Alexander E, Carsons S, et al. Classification criteria for Sj¨ogren’s syndrome: a revised version of the European criteria proposed by the American-European consensus group. Ann Rheum Dis 2002;61:554-8. [28] Shiboski S, Shiboski C, Criswell A, Baer A, Challacombe S, Lanfranchi H, et al. American college of Rheumatology classification criteria for Sj¨ogren’s syndrome: a data-driven expert consensus approach in the Sj¨ogren’s international collaborative clinical alliance cohort. Arthritis Care Res 2012;4:475-87. [29] Seror R, Ravaud P, Bowman S, Baron G, Tzioufas A, Theander E, et al. EULAR Sj¨ogren’s syndrome disease activity index (ESSDAI): development of a consensus systemic disease activity index for primary Sj¨ogren’s syndrome. Ann Rheum Dis 2009;69:1103-9. [30] Kalk W, Vissink A, Stegenga B, Bootsma H, Nieuw A, Kallenber C. Sialometry and sialochemestry: a non-invasive approach for diagnosing Sj¨ogren’s syndrome. Ann Rheum Dis 2002;61: 137-44. [31] Kalk W, Vissink A, Spijkervet F, Bootsma H, Kallenberg C, Nieuw A. Sialometry and sialochemestry: diagnostic tools for Sj¨ogren’s syndrome. Ann Rheum Dis 2001;60:1110-6. [32] Al-Hashimi I, Haghighat N, Fox P. Salivary electrophoresis in the diagnosis of Sj¨ogren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endodon 1998;85:542-7. [33] el-Miedany Y, el-Hady S, el-Baddin M. Validity of the saliva ferning test for the diagnosis of dry mouth in Sj¨ogren’s syndrome. Rev Rheum Engl Ed 1999;66:73-8. [34] Inamura T, Ino C, Katoh M, Kishimoto A, Kumazawa H, Matsumoto A, et al. A simple method to estimate the secretion of saliva from minor salivary glands using iodine-starch reaction. Laryngoscope 2001;111:272-7. [35] Dawes C. Physiological factors affecting salivary flow rate, oral sugar clearance and the sensation of dry mouth in men. J Dent Res 1987;66:648-53. [36] Sa´nchez-Guerrero J, Aguirre-Garcia E, Pe´rez-Dosal M, Kraus A, Cardiel M, Soto-Rojas A. The wafer test: a semi-quantitative test to screen for xerostomia. Rheumatology 2002;41:381-9. [37] Kohler P, Winter M. A quantitative test for xerostomia. The Saxon test, an oral equivalent of the Schirmer test. Arthritis Rheum 1985;28:1128-32. [38] Lo´pez-Jornet P, Camacho-Alonso F, Bermejo-Fenoll A. A simple test for salivary gland hypofunction using oral Schirmer’s test. J Oral Pathol Med 2006;35:244-8. [39] Sreebny L, Valdini A. Xerostomia part I: relationship to other oral symptoms and salivary gland hypofunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endodon 1988;66:451-8. [40] Ma´rton K, Boros I, Varga G, Zelles T, Feje´rdy P, Zeher M, et al. Evaluation of palatal saliva flow rate and oral manifestations in patients with Sj¨ogren’s syndrome. Oral Dis 2006;12:480-6. [41] Skopouli FN, Siouna-Fatourou HI, Ziciadis C, Moutsopoulos HM. Evaluation of unstimulated whole saliva flow rate and stimulated parotid flow as confirmatory test for xerostomia. Clin Exp Rheumatol 1989;7:127-9. [42] Kanehira T, Yamaguchi T, Asano K, Morita M, Maeshima E, Matsuda A, et al. A screening test for capsaicin-stimulated salivary flow using filter paper: a study for diagnosis of hyposalivation with a complaint of dry mouth. Oral Surg Oral Med Oral Pathol Oral Radiol Endodon 2011;112:73-80. [43] Speight P, Kaul A, Melson R. Measurement of whole unstimulated saliva flow in the diagnosis of Sj¨ogren’s syndrome. Ann Rheum Dis 1992;51:499-502. [44] Pennec Y, Letoux G, Leroy J, Youinou P. Reappraisal of test for xerostomia. Clin Exp Rheumatol 1993;11:523-8.

G. Herna´ndez-Molina and T. Sa´nchez-Herna´ndez [45] Bookman A, Shen H, Cook R, Bailey D, McComb R, Rutka J, et al. Whole stimulated salivary flow: correlation with the pathology of inflammation and damage in minor salivary gland biopsy specimens form patients with primary Sj¨ogren’s syndrome but not patients with sicca. Arthritis Rheum 2011;63:2014-20. [46] Shiffman R, Christanson M, Jacobsen G. Reliability and validity of the ocular surface disease index. Arch Ophthamol 2000;118:615-21. [47] Begley C, Caffery B, Chalmers R, Mitchell G, the Dry Eye Investigation (DREI) Study Group. Use of the dry eye questionnaire to measure symptoms of ocular irritation in patients with aqueous tear deficit dry eye. Cornea 2002;21(7):664-70. [48] Thomson WM, Chalmers JM, Spencer AJ, Williams SM. The xerostomia inventory: a multi-item approach to measuring dry mouth. Community Dent Health 1999;16:12-7. [49] Bowman S, Booth D, Platts R, Field A, Rostron J, UK Sj¨ogren’s Interest Group. Validation of the sicca symptoms inventory for clinical studies of Sj¨ogren’s syndrome. J Rheumatol 2003;30: 1259-66. [50] Bowman S, Booth D, Platts R, UK Sj¨ogren’s Interest Group. Measurements of fatigue and discomfort in primary Sj¨ogren’s syndrome using a new questionnaire tool. Rheumatology 2004;43:758-64. [51] Holly F. Dry eye and the Sj¨ogren’s syndrome. Scand J Rheumatol 1986(Suppl. 61):201-5. [52] Mackie I, Seal D. Confirmatory tests for the dry eye of Sj¨ogren’s syndrome. Scand J Rheumatol 1986(Suppl. 61):220-3. [53] Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, et al. EULAR Sj¨ogren’s syndrome patient reported index (ESSPRI): development of a consensus patient index for primary Sj¨ogren’s syndrome. Ann Rheum Dis 2011;70:968-72. [54] Bowman S, Sutcliffe N, Isenberg D, Goldblatt F, Adler M, Price E, et al. Sj¨ogren’s syndrome clinical activity index (SCAI) a systemic disease activity measure for use in clinical trials in primary Sj¨ogren’s syndrome. Rheumatology 2007;46:1845-51. [55] Ware J, Snow K, Kosinki M, Gandek B. SF-36 health survey. Manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Centre, 1993. [56] Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. Validation of the functional assessment of chronic illness therapy fatigue scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-9. [57] Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, et al. Development of a fatigue scale. J Psychosom Res 1993;37:147-53. [58] Smets E, Garssen B, Bonke B, De Haes J. The multidimensional fatigue inventory psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315-25. [59] Krupp L, LaRocca N, Muir-Nash J, Steinberg A. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:112-3. [60] Fisk J, Ritvo P, Ross L, Haase D, Marrie T, Sclhech W. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994;18(Suppl. 1): S79-S83. [61] Berendregt P, Visser M, Smets E, Tulen J, van den Meiracker A, Boosma F, et al. Fatigue in primary Sj¨ogren’s syndrome. Ann Rheum Dis 1998;57:291-5. [62] Lwin C, Bishay M, Platts R, Booth D, Bowman S. The assessment of fatigue in primary Sj¨ogren’s syndrome. Scand J Rheumatol 2003;32:33-7.

639 [63] Bowman S, Hamburger J, Richards A, Barry R, Rauz S. Patientreported outcomes in primary Sj¨ogren’s syndrome: comparison of the long and short versions of the profile of fatigue and discomfort-sicca symptoms inventory. Rheumatology 2009;48: 140-3. [64] Sutcliffe N, Stoll T, Pyke S, Isenberg D. Functional disability and end organ damage in patients with SLE, SLE and Sj¨ogren’s syndrome and primary SS. J Rheumatol 1998;25:63-8. [65] Group EuroQol. EuroQoL a new facility for the measurement of health related quality of life. Health Policy 1999;16; 199-208. [66] Slade G, Spencer A. Development and evaluation of the oral health impact profile. Community Dent Health 1994;11:3-11. [67] Schiffman R, Christianson M, Jacobsen G, Hirsch J, Reis B. Reliability and validity of the ocular surface disease index. Arch Ophthamol 2000;118:615-21. [68] Abetz L, Rajagopalan K, Mertzanis P, Begley C, Barnes R, Chalmers R, et al. Impact of dye eye on everyday life (IDEEL) study group. Development and validation of the impact of dry eye on everyday life (IDEEL) questionnaire, a patient-reported outcome (PRO) measure for the assessment of the burden of dry eye on patients. Health Qual Life Outcomes 2011;9:111. [69] Rajagopalan K, Abetz L, Mertzanis P, Espindle D, Begley C, Chalmers R, et al. Comparing the discriminative validity of two generic and one disease-specific health-related quality of life measures in a sample of patients with dry eyes. Value Health 2005;8:168-74. [70] Campar A, Isenberg D. Primary Sj¨ogren’s syndrome activity and damage indices comparison. Eur J Clin Invest 2010;40:636-44. [71] Asmussen K, Andersen V, Bendien G, Bendtzen K, Prause J, Thorn J, et al. Quantitative assessment of clinical disease status in primary Sj¨ogren’s syndrome. Scand J Rheumatol 1997;26: 197-205. [72] Vitali C, Bencivelli W, Isenberg D, Smolen J, Snaith M, Sciuto M, et al. Disease activity in systemic lupus erythematosus: report of the consensus study group of the European workshop for rheumatology research. Identification of the variables indicative of disease activity and their use in the development of an activity score. Clin Exp Rheumatol 1992;10:541-7. [73] Hay E, Bacon P, Gordon C, Isenberg D, Madison P, Snaith J, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med 1993;86(7):447-58. [74] Seror R, Marriette X, Bowman S, Baron G, Gottenberg J, Boostma H, et al. Accurate detection of changes in disease activity in primary Sj¨ogren’s syndrome by the European league against rheumatism Sj¨ogren’s syndrome disease activity index. Arthritis Care Res 2010;62:551-8. [75] Meiners P, Arends S, Brouwer E, Spikervet F, Vissink A, Bootsma H. Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sj¨ogren’s syndrome treated with rituximab. Ann Rheum Dis 2012;71:1297-302. [76] Barry R, Sutcliffe N, Isenberg D, Price E, Goldblatt F, Adler M, et al. The Sj¨ogren’s syndrome damage index- a damage index for use in clinical trials and observational studies in primary Sj¨ogren’s syndrome. Rheumatology 2008;47:1193-8. [77] Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. Systemic lupus international collaborative clinics: development of a damage index in systemic lupus erythematosus. J Rheumatol 1992;19:1820-1.