Vera Milic

Diagnostic Value of Salivary Gland Ultrasonographic Scoring System in Primary Sjögren’s Syndrome: A Comparison with Scintigraphy and Biopsy

Objective. To compare an ultrasonographic (US) scoring system of salivary glands with scintigraphy and salivary gland biopsy, in order to evaluate its diagnostic value in primary Sjögren’s syndrome (SS). Methods. In 135 patients with suspected SS, the grades of 5 US measures of both parotid and submandibular salivary glands were scored (0–48 scale). Diagnosis of primary SS was established following the American-European Consensus Group criteria of 2002. The patients’ total scintigraphic score (0–12 scale) was determined and the histopathological changes of minor salivary glands graded. Area under the receiver-operating characteristic (ROC) curve was employed to evaluate the diagnostic value of the US scoring system. Results. Primary SS was diagnosed in 107 (79.2%) patients and the remaining 28 subjects (20.8%) constituted the control group. US changes of salivary glands were established in 98/107 patients with SS and in 14/28 controls. Mean US score was 26 in SS patients and 6 in controls. Through ROC curves, US arose as the best performer (0.95 ± 0.01), followed by scintigraphy (0.86 ± 0.31). Setting the cutoff score for US at 19 resulted in the best ratio of specificity (90.8%) to sensitivity (87.1%), while setting the cutoff scintigraphic score at 6 resulted in specificity of 86.1% and sensitivity of 67.1%. Among 70 patients with US score ≥ 19, a scintigraphic score > 6 was recorded in 54/70 (77.1%) and positive biopsy findings in 62/70 (88.5%) patients. Conclusion. We show high diagnostic accuracy of a novel US scoring system of salivary glands (0–48) in patients with primary SS comparable to invasive methods, i.e., scintigraphy and salivary gland biopsy.

Ultrasonography of major salivary glands could be an alternative tool to sialoscintigraphy in the American–European classification criteria for primary Sjögren's syndrome

OBJECTIVE To test the diagnostic accuracy of modified American-European classification criteria (AEC) for primary SS (pSS) by replacing sialoscintigraphy (sSC) with ultrasonography of the major salivary glands. METHODS One hundred and ninety subjects were evaluated for the diagnosis of pSS, including US of the salivary glands. We tested the diagnostic accuracy of the three different sets of five diagnostic criteria for pSS. Each set combined these four criteria (ocular symptoms, oral symptoms, Schirmer-I test and auto-SS-A antibody) and one of the following: US (US set), sSC (sSC set) or biopsy (Biopsy set). The area under the receiver operating characteristics curve (AUC-ROC) was used to evaluate the diagnostic accuracy of each set of criteria. RESULTS Out of 190 subjects examined, 140 subjects fulfilled the AEC for the diagnosis of pSS, whereas 50 subjects were classified as non-pSS subjects. US score was positive in 129 (92%), sSC in 123 (88%) and biopsy in 93 (66%) of 140 pSS patients. Among 140 patients with pSS, 88 (63%) patients fulfilled the criteria of the US set, 85 (61%) patients of the sSC set and 71 (51%) patients of the Biopsy set. None of the subjects from the non-pSS group fulfilled any of the sets of criteria. Diagnostic accuracy of each of the three sets of criteria was high and similar [AUC-ROC (s.e.) for the US set was 0.99 (0.00), followed by the sSC set at 0.98 (0.00) and the Biopsy set at 0.97 (0.00)]. CONCLUSION US finding of major salivary gland involvement could replace sSC in AEC for the diagnosis of pSS.

Is salivary gland ultrasonography a useful tool in Sjögren’s syndrome? A systematic review

OBJECTIVE Ultrasonography (US) is a sensitive tool in the diagnosis of major salivary gland abnormalities in primary Sjögrens syndrome (pSS). The aim of this systematic review was to assess the metric properties of this technique. METHODS PUBMED and EMBASE databases were searched. All publications between January 1988 and January 2013 were considered. Data were extracted from the articles meeting the inclusion criteria according to US definition of salivary gland scoring system and metric properties studied. The type and number of glands tested, study design and metric properties according to OMERACT filter (truth, discrimination, feasibility) were assessed. RESULTS Of 167 publications identified initially with PUBMED and EMBASE, 31 met the inclusion criteria. The number of pSS patients varied among the studies from 16 to 140. The diagnosis of pSS was in line in most of the cases with the American-European Consensus Group (AECG) classification criteria for Sjögrens syndrome. The US examination was performed in suspected pSS only in studies in which the sensitivity ranged from 45.8 to 91.6% and specificity from 73 to 98.1%. There was heterogeneity in regard to the definition of US in B-mode and few studies used US in colour Doppler. Few studies reported reliability of US and sensitivity to change in pSS. CONCLUSION US is a valuable tool for detecting salivary gland abnormalities in pSS. Its reliability has been poorly investigated and there is considerable variation in the definition of US abnormalities. Further studies are required to validate and standardize the US definition of salivary gland in pSS.

Salivary gland ultrasound abnormalities in primary Sjögren’s syndrome: consensual US-SG core items definition and reliability

Objectives Ultrasonography (US) is sensitive for detecting echostructural abnormalities of the major salivary glands (SGs) in primary Sjögren’s syndrome (pSS). Our objectives were to define selected US-SG echostructural abnormalities in pSS, set up a preliminary atlas of these definitions and evaluate the consensual definitions reliability in both static and acquisition US-SG images. Methods International experts in SG US in pSS participated in consensus meetings to select and define echostructural abnormalities in pSS. The US reliability of detecting these abnormalities was assessed using a two-step method. First 12 experts used a web-based standardised form to evaluate 60 static US-SG images. Intra observer and interobserver reliabilities were expressed in κ values. Second, five experts, who participated all throughout the study, evaluated US-SG acquisition interobserver reliability in pSS patients. Results Parotid glands (PGs) and submandibular glands (SMGs) intra observer US reliability on static images was substantial (κ > 0.60) for the two main reliable items (echogenicity and homogeneity) and for the advised pSS diagnosis. PG inter observer reliability was substantial for homogeneity. SMGs interobserver reliability was moderate for homogeneity (κ = 0.46) and fair for echogenicity (κ = 0.38). On acquisition images, PGs interobserver reliability was substantial (κ = 0.62) for echogenicity and moderate (κ = 0.52) for homogeneity. The advised pSS diagnosis reliability was substantial (κ = 0.66). SMGs interobserver reliability was fair (0.20< κ ≤ 0.40) for echogenicity and homogeneity and either slight or poor for all other US core items. Conclusion This work identified two most reliable US-SG items (echogenicity and homogeneity) to be used by US-SG trained experts. US-PG interobserver reliability result for echogenicity is in line with diagnosis of pSS.

Polymorphisms of the eNOS gene are associated with disease activity in rheumatoid arthritis

Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction–restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course.

Multiobserver Reliability of Ultrasound Assessment of Salivary Glands in Patients with Established Primary Sjögren Syndrome

Objective. To evaluate the multiobserver reliability of salivary gland ultrasonography (SGUS) for scoring greyscale (GS) parenchymal inhomogeneity and parenchymal color Doppler (CD) signal in patients with established primary Sjögren syndrome (pSS). Methods. The study comprised 2 multiobserver reliability assessments in patients with pSS in 2 European centers. The first reliability exercise was performed on 24 patients with pSS and 8 controls who were independently evaluated with GS and CD US by 5 observers at the Institute of Rheumatology, Belgrade, Serbia. The second reliability exercise was carried out on 10 patients with pSS who were independently assessed with GS and CD US by 8 observers at the Hospital G.U. Gregorio Marañón, Madrid, Spain. SGUS parenchymal inhomogeneity and parenchymal CD signal were semiquantitatively scored using a 4-grade scoring system. The multiobserver agreement was calculated by the overall agreement and Light’s κ statistics. Results. A total of 640 SGUS examinations were performed in the first reliability exercise and a total of 320 examinations in the second reliability exercise. Multiobserver reliability was good (κ = 0.71–0.79) to excellent (κ = 0.81–0.82) for GS parenchymal inhomogeneity in both exercises. There was a moderate (κ = 0.53–0.58) to good (κ = 0.70) multiobserver reliability for parenchymal CD signal in the first exercise. However, there was no agreement or only a fair agreement (κ = 0.03–0.29) for parenchymal CD signal in the second exercise. Conclusion. US may be a reliable technique in the multiobserver scoring of GS parenchymal inhomogeneity of major SG in patients with established pSS. CD scoring of SG needs further standardization to be used in multicenter studies.

Automating evaluation of salivary gland ultrasound images in PSS patients using the scattered transform algorithm - a pilot study

Background Primary Sjögrens syndrome (pSS) is an autoimmune inflammatory disease predominantly affecting the salivary and lacrimal glands. The main symptoms are dryness of the mouth and eyes. The diagnosis of pSS is based on 6 items according to the American-European consensus group (AECG) classification criteria. Interest regarding ultrasonography (US) as a diagnostic tool for pSS has increased over the last years. However, the applied scoring-systems vary and as of yet international consensus on how to perform the evaluation are lacking. Consequently, the examination and evaluation depends on the examiners skill and experience. In both clinical work and a scientific setting there is a need to use objective methods with as little inter- and intra-examiner variation as possible. Objectives The aim of this study was to develop a software able to analyze changes in digitally stored US images of the major salivary glands. Methods Digitally stored US images of glandula parotis (n=94) were blindly evaluated and scored as “normal” or “SS-like” by three independent clinical researchers. At least 2/3 evaluations had to be in agreement to classify the image. All images were from patients fulfilling the AECG criteria. Images had been obtained by six clinical investigators using similar protocols on different US machines. For the analysis, images were divided into databases of SS-like changes and normal-appearing morphology. The image classification and analysis was performed using the ScatNet (v.02) algorithm (Ref: http://www.di.ens.fr/data/software/)for MatLab, which is an algorithm for advanced pattern recognition. Images from the databases were randomly selected to be used as either “training” images or “test” images. Each database of “training” images was analysed, and features of pathological and non-pathological morphology were identified by the software. For the software test, the algorithm analyses which of the databases of training images are most similar to the test images and decides in which group the test images belong. This selection was then compared to the manual scoring. Results Out of the 94 images evaluated, 40 were classified as normal-appearing and 54 as corresponding to SS-like pathological changes. In the preliminary simulations we have used the following training: test ratios 84:10 (90%), 70:24 (75%) and 47:47 (50%), to respectively train the classification algorithm, and then test the algorithm. The best result with 9/10 correctly classified (92% accuracy) was obtained using 90% of the images to train the software and 10% to test the software. Using 75% or 50% of the images to train the software, the accuracy was reduced to 21/24 (88%) and 25/36 (78%), respectively. Conclusions Preliminary results indicate that the success rate of the algorithm is closely dependent on the number of images used to train the algorithm. The results are promising and indicate possible clinical use in the evaluation of SGUS images. We will further focus on expanding the image database to achieve more precise results. Disclosure of Interest None declared

Cerebellar ataxia in a patient with primary Sjögren's syndrome after treatment with chloroquine.

Dear Editor, We report a 65-year-old female patient with primary Sjögren’s syndrome, who developed cerebellar ataxia during treatment with chloroquine. From 1993 to 2006 the patient was observed at the Institute of Rheumatology, Belgrade, Serbia, as having undiVerentiated connective tissue disease. Through this period she had painful joints, intermittent arthritis, recurrent urticaria and positive antinuclear antibodies (1/320). Because the diagnosis was unclear, she was treated for many years only with non-steroidal anti-inXammatory drugs (NSAID). However, in 2004 the patient started to take chloroquine 250 mg daily. Every 6 months she was advised to stop the treatment for 4 weeks and was examined by an ophthalmologist to exclude potential side eVects of the drug. In 2006, symptoms of dry eyes and mouth appeared and she was found to have positive rheumatoid factor, ANA and anti-SS-A antibodies. Schirmer’s and Rose-Bengal tests were positive. Decreased uptake and secretion of 99 m-technetium sodium pertechnetate in submandibular glands was noticed. Typical histological pattern for primary Sjögren’s syndrome (grade IV on Mason–Chisholm scale) was found after minor salivary gland biopsy [1]. The patient continued to take chloroquine and NSAID. In March 2007, she presented with transitory right-side hemiparesis, which appeared 1–2 times a week, lasting for about 2 h. She felt very unstable when walking. No headache or unconsciousness was reported. Apart from Sjögren’s syndrome, she had also a history of arterial hypertension for about 8 years and peripheral paralysis of the left facial nerve in 2005. A cerebrovascular insult due to hypertension or cerebral vasculitis as clinical feature of Sjögren’s syndrome was expected, but endocranial CT scan revealed extensive cortical atrophy in the frontal part of the brain, as well as atrophy of the cerebellum and vermis. The patient was hospitalized and further examined at the Institute of Neurolgy, Belgrade, Serbia. Ataxia, right-side bradyteleokinesis and hypodiadochokinesis were observed. Cranial nerves were found to be normal, except a residual paresis of the left facial nerve. Muscular hypotonus on both the arms was present, with symmetrically increased reXexes. Patient’s right arm sunk and set below the left arm, when Wartenberg pendulum test was performed. Muscular tonus and deep tendon reXexes on legs were normal. Paraneoplastic syndrome and dysfunction of the thyroid gland, as possible causes of brain atrophy, were excluded. Laboratory results (including analysis of the cerebrospinal Xuid), chest X-ray and abdominal ultrasound Wndings were normal. After complete examination, idiopathic cerebellar ataxia with late onset was diagnosed. Treatment with chloroquine was stopped. Despite treatment discontinuation, neurological Wndings were unchanged. In February 2008, the patient underwent endocranial MRI, which revealed cortical atrophy in the frontoparietal part of the brain, in the cerebellum (especially in the left hemisphere) and vermis, with consequently dilatation of the ventricular system and subarachnoid space. The patient is now treated with vitamins and Aspirin 100 mg daily. She continued to take artiWcial tears and NSAID. It is believed that chloroquine is a relatively safe drug, but it is necessary to examine patients for potential side V. Milic Clinical Rheumatology IVb, Institute of Rheumatology, Belgrade, Serbia

INTEGRATION OF SALIVARY-GLAND ULTRASONOGRAPHY IN CLASSIFICATION CRITERIA FOR PRIMARY SJOGREN'S SYNDROME: AN INTERNATIONAL VIGNETTE-BASED STUDY

Background The recent classification criteria sets for primary Sjögrens syndrome (AECG 2002 and ACR/EULAR 2017) did not include major salivary glands ultrasononography (SGUS). Objectives The UTOPIA study was undertaken to determine if and how SGUS may improve the ACR/EULAR criteria. Methods Twenty four international experts in pSS evaluated on an internet-secure relational database 512 randomly realistic vignettes derived from 150 patients with suspected pSS included in the french DiapSS cohort. Each vignette contained sections on “history” (duration of the symptoms, gender, age), clinical symptoms (dry mouth, dry eyes and systemic manifestations), results of the SGUS evaluation (score > ou < to 2), and results of the major tests to diagnose pSS (Schirmers test, ocular staining score (OSS), salivary flow, focus score on salivary biopsy, presence of anti-SSA antibodies). Each expert had to score the diagnosis of pSS as absent, unlikely, likely or present for 64 vignettes. Each vignette was evaluated by 3 experts. Diagnosis of pSS was obtained when at least 2 of 3 considered it as likely or present. Univariate and multivariate analysis (Wald test) were performed to evaluate the association between the SGUS criteria, the ACR/EULAR criteria and its different individual items with the diagnosis of pSS as defined by the experts. Data were then replicated on independent cohorts of suspicion of pSS. Results Univariate and multivariate analyses confirmed that ACR/EULAR criteria and SGUS were independently associated with the diagnosis of pSS. Disease duration, OSS and ocular dryness were not associated with the diagnosis of pSS. Only 6 variables were selected by logistic regression analysis: presence of anti-SSA (weight:4), focus score (weight:3), SGUS (weight:2), Schirmers test (weight:1), dry mouth (weight:1) and salivary flow rate (weight:1). According to ROC curve analysis, a score of ≥5 had 96% Se and 84% Sp, compared with 90% Se and 84% Sp for the ACR/EULAR criteria. The corrected C statistic (AUC) for the new weighted score was 0.98. Conclusions Inclusion of the SGUS item in the ACR/EULAR criteria improves their diagnostic performance. Disclosure of Interest S. Jousse-Joulin: None declared, F. Gatineau: None declared, C. Baldini: None declared, S. Arends: None declared, F. Barone: None declared, A. Baer: None declared, H. Bootsma: None declared, S. Bowman: None declared, P. Brito-Zeron: None declared, D. Cornec: None declared, T. Dorner: None declared, S. De Vita: None declared, B. Fisher: None declared, D. Hammenfors: None declared, M. Jonsson: None declared, X. Mariette: None declared, V. Milic: None declared, T. Nakamura: None declared, W.-F. Ng: None declared, E. Nowak: None declared, A. Rasmussen: None declared, R. Seror: None declared, C. Shiboski: None declared, T. Nakamura: None declared, M. Ramos-Casals: None declared, A. Vissink: None declared, A. saraux: None declared, V. Devauchelle-Pensec Grant/research support from: ROCHE-CHUGAI

SAT0328 Big-Five Personality in Sjogren Syndrome – Association with ESSPRI

Background The severity of symptoms of dryness, pain and fatigue may be determined by psychological features patients with Sjogrens syndrome (SS). The Big-Five framework is a widely examined model which represent personality at the broadest level of abstraction. The NEO Personality Inventory-Revisited (NEO-PI-R) is frequently used questionnaire to assess the Big-Five domains: Neuroticism (N), Extraversion (E), Openness to Experience (O), Agreeablenes (A) and Conscientiousness (C). Objectives To Big-Five analyse of personality of SS patients and association with the severity of dryness, pain and fatigue measured by ESSPRI (EULAR SS Patient Reported Index). Methods One hundred and five patients with confirmed SS by AECG criteria (mean age 51,34 years, mean disease duration 5,98 years) and fifty-four healthy controls (mean age 51,35 years) participated in study. All participants were females and provided written informed consent. The diseasy activity was measured by ESSDAI (EULAR SS disease activity index) and ESSPRI. All participants filled out the sociodemographic questionnaire (age, educational level, work and marital status, residence, social support and comorbidity). The Big-Five personality traits were measured using NEO-P-R. The 240 items are answered on a 5-point Likert scale ranging from strongly disagree to strongly agree. The analysis was performed using the SPSS program (version 16.0). Data were examined by independent t-test, Chi-square test and Mann-Whitney test. The association of the Big Five personality traits with the ESSPRI was examined using linear regression analyses. A p-value <0.05 was considered significant. Results Statistical significant differences between two groups were observed in educational level (p=0.001), work status (p=0.001), residence (p=0.001) and social support (p=0.05), but they did not different in age, marital status and comorbidity (p>0.05). In SS patients, the median of ESSDAI was 6 (range 4–11), the median ESSPRI was 5.33 (range 3.66–6.66). Compared to healthy controls, SS patients showed significatly higher scores in N (94.76 vs. 84.63, p=0.006) and lower E (94.79 vs.104.20, p=0.002) and O (101.86 vs. 111.17, p=0.05) domens. Scores A and C were similare in groups (120.48 vs 121.04 and 122.97 vs. 125.02, p>0.05). Futher, E and O domens were significantly associated with ESSPRI (p=0.008, p=0.000), while N was borderline (p=0.056). After adjustment for confounding variables, only E domen remained significantly associated with ESSPRI (p=0.01). The analyse showed that E domen was negatively associated with age (B= -0.341, p=0.013), unmarital status (B= -4.317, p=0.013) and positive associated with social support (B=7.952, p=0.013). Conclusions Patients with SS had a higher levels of Neuroticism and lower levels of Extraversion and Opennes to experiences compared to healthy persons. In SS patients, Extraversion and Openness were associated with severity of symptoms of dryness, pain and fatigue. The social support is significantly associated with higher level Extraversion, in contrast to older and single individuals. Disclosure of Interest None declared