RElevance of UltraSonography for Assessing Salivary Gland Involvement in Systemic Sclerosis (SSc) (REUSSI-SSc)

As fibrosis of salivary glands is supposed to be the main mechanism involved in Systemic sclerosis (SSc)-associated sicca syndrome, Ultrasonography , biopsy and measuring gland elasticity (by ARFI (Acoustic Radiation Force Impulse)) in SSc patients could also constitute a relevant method to assess the potential alterations of echostructure of major salivary glands and the fibrosis of Salivary Glands in this disease.

Systemic sclerosis (SSc) is a rare autoimmune chronic disorder characterised by vascular hyper-reactivity and fibrosis of the skin as well as internal organs. Intimal hyperplasia, endothelial dysfunction and occlusive vasculopathy are the underlying basis of these chronic vascular damages. The expression of the vasculopathy especially includes Raynaud phenomenon (RP), digital ulcers (DUs), gastro-intestinal involvement and pulmonary arterial hypertension (PAH). Sicca syndrome is clinically characterised by dryness of the eyes (xerophthalmia) and mouth (xerostomia). The prevalence of sicca symptoms is up to 70% in prospective series of SSc patients. Sicca syndrome is supposed to be primarily related to glandular fibrosis. The prevalence of primary Sjögren Syndrome (pSS) among SSc patients, as defined by the American-European Consensus Group criteria is around 15%. Sicca syndrome is therefore a frequent feature in SSc and constitutes an important cause of quality of life's impairment in SSc If studies have already evaluated clinical and histological alterations of minor salivary glands secondary to sicca syndrome in SSc , only few studies used the recent ACR(American College of Rheumatology) 2013 classification criteria for SSc to select patients. SGUS(Salivary Gland UltraSonography) evaluation in SSc has never been assessed to date. Potential alterations of MSG (Major Salivary Gland) echostructure in SSc have never been described to date. The performances and reliability of SGUS to assessed MSG involvement in SSc are still to be determined. As fibrosis of salivary glands is supposed to be the main mechanism involved in SSc-associated sicca syndrome, measuring salivary-gland elasticity using ARFI-ultrasonography in SSc patients could also constitute a relevant method to assess the fibrosis of MSG in this disease. A cross-sectional pilot study is therefore needed to explore these relevant questions about sicca syndrome in SSc.

The examiner performin the evaluation of ultrasound features of the main salivary glands will not have acess at the first part of patient evaluation.

HAQ(Health Assessment Questionnaire) Score, bilateral schirmer 's test, unstimulated whole salivary flow rate, blood sample for immunologic evaluation

HAQ(Health Assessment Questionnaire) score, bilateral schirmer 's test, unstimulated whole salivary flow rate, blood sample for immunologic evaluation

Ultrasonography characteristics of major salivary glands based on Salaffi's composite score. each MSG will be scored as followed: grade 0 = normal homogeneous glands; grade 1 = Homogenous borders, slightly heterogeneous parenchyma, grade 2 = Homogenous borders, multiple hypoechogenic areas measuring < 2 mm, grade 3 = multiple hypoechogenic areas measuring 2-6 mm or irregular borders or invisible posterior part of the gland; grade 4 = unstructured glandular parenchyma with multiple hypoechogenic areas measuring >6 mm or calcifications with echogenic bands. In each patient, 4 grades can be obtained (1 grade per gland); the sum of these 4 grades (range 0-16) will be the Salaffi's score. A score of 0 has the best outcome, of 16 the worse

Ultrasonography characteristics of major salivary glands based on bilateral ARFI(Acoustic radiation force Impulse) elastometry

Scores of Hocevar,based on the same ultrasound parameters but with a weighting different from that of Salaffi in the calculation of the score. Echostructure of the four salivary glands will be graded 0 to 12 ; the sum of these 4 grades (range 0-48) will be the Hocevar's score. A score of 0 has the best outcome, of 48 the worse.

Scores of Milic,based on the same ultrasound parameters but with a weighting different from that of Salaffi in the calculation of the score. Echostructure of the four salivary glands will be graded 0 to 3 ; the sum of these 4 grades (range 0-12) will be the Milic's score. A score of 0 has the best outcome, of 12 the worse.

Scores Jousse-Joulin / Cornec constituting , based on the same ultrasound parameters but with a weighting different from that of Salaffi in the calculation of the score. Echostructure of the four salivary glands will be graded 0 to 4 ; the sum of these 4 grades (range 0-16) will be the Jousse-Joulin/Cornec's score. A score of 0 has the best outcome, of 16 the worse.

Biopsies of the minor salivary glands with standardized histological characterization of the Chisholm score. Chisholm'score will evaluate the number of lymphocytic foci/4mm2 grade 1 : none or slight, grade 2 : less than 50 lymphocytes and histocytes, grade 3 : one focus with at least 50 lymphocytes, grade 4 : More than one focus with at least 50 lymphocytes, Grade 1 has the best outcome, grade 4 the worse.

Biopsies of the minor salivary glands with standardized characterization of the focus score. Focus score : the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section, Focus score 0 = no mononuclear cell infiltrate containing at least 50 inflammatory cells in a 4 mm2 glandular section, Focus score =1 or >1 : one or more mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section, Focus score 0 has the best outcome Focus score =1 or >1 has the worse outcome

Evaluation of the presence or absence of objective criteria of Sjogren according to salivary flow test

visceral damage : Presence or absence of pulmonary involvement on CT scan, Presence or absence of pulmonary arterial hypertension on echocardiography.

immunological data : Positivity of : Anti SSA(Anti Sjögren Syndrom A) antibodies,Anti SSb(Anti Sjögren syndrom B) antibodies,Anti Topoisomerase antibodies, Anti Centromere antibodies, Anti RNA polymerase III antibodies Using Indirect ImmunoFluorescence (IFI) ( as binary parameter (positive or negative)

Inclusion Criteria: Patients over eighteen years old; Fulfilling 2013 ACR classification criteria for Systemic sclerosis (Van den Hoogen et al. 2013); 60 patients with subjective sicca symptoms reported by a standardised questionnaire (Vitali C et al. 2002); 15 patients without sicca symptoms; Who has signed an informed consent Benefiting from a social security scheme Exclusion Criteria: Treatment: current (or in the past 6 months) immunosuppressive treatment by rituximab or cyclophosphamide (representing less than 5% of SSc patients in the investigator's centres); Current (or in the past 6 months) treatment with drugs with anti-cholinergic properties (Selective Serotonin Reuptake Inhibitors and anti-histaminic inhibitors (hydroxyzine)); Current treatment with antiplatelet aggregates Anti-vitamin K treatment (increasing risk of bleeding during minor salivary gland biopsy); and oral anti-coagulant Known abnormal coagulation (prolonged aPPT(activated partial thromboplastin time) and / or PT (Prothrombin time ( <70%)), or known thrombocytopenia (<150,000 platelets / mm3) Known secondary sicca symptoms : history of head-and-neck radiotherapy, hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-vs-host disease and IgG4(Isotype's immunoGlobulin G4)-related disease; Pregnancy or breastfeeding mothers; Known intolerance/allergy to xylocain injection; Adults legally protected (under judicial protection, guardianship, or supervision), inability to consent.

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