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OBJECTIVES: To explore Patient Acceptable Symptom State (PASS) in a standard of care cohort of patients with primary Sjögren's syndrome (pSS) and to compare patient characteristics including EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) between PASS and non-PASS groups.METHODS: All pSS patients fulfilling ACR/EULAR classification criteria from the Registry of Sjögren's Syndrome LongiTudinal (RESULT) cohort, who had available PASS data at baseline were included. Patient-reported outcomes included the PASS question: "Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?"; yes: PASS / no: non-PASS.RESULTS: Of the 278 included pSS patients, 199 (72%) had an acceptable symptom state according to the PASS question, and median ESSPRI was 6 (IQR 4-7). In the PASS group, 118 (59%) patients had an unacceptable symptom state according to ESSPRI (score ≥5). In multivariable regression analyses, ESSPRI and disease duration were independently associated with presence of PASS. The accuracy of ESSPRI to predict PASS was fair (AUC of 0.78). The cut-off point of ESSPRI for presence of PASS with the highest Youden's index was 7.2 (sensitivity 85%, specificity 56%), followed by 5.2 (sensitivity 48%, specificity 90%).CONCLUSIONS: The majority of pSS patients reported being in an acceptable symptom state according to the PASS question, despite high ESSPRI scores. In our standard of care cohort, the optimal cut-off point of ESSPRI to predict PASS is different when focusing on sensitivity (±7) or specificity (±5).

ObjectiveTo investigate salivary gland ultrasound (SGUS) abnormalities in relation to clinical phenotype and patient characteristics, disease activity, and disease damage in patients with primary Sjögren syndrome (pSS).MethodsConsecutive outpatients included in our REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort were selected. Patients with pSS who were included were classified according to the American College of Rheumatology/European League Against Rheumatism (EULAR) criteria and underwent full ultrasonographic examination (Hocevar score 0–48) at baseline. Total SGUS scores of ≥ 15 were considered positive. Patient characteristics, disease activity, and disease damage were compared between the different SGUS groups.ResultsIn total, 172 of 186 patients with pSS were eligible, of whom 136 (79%) were SGUS positive. Compared with patients who were SGUS negative, SGUS-positive patients had significantly longer disease duration, higher EULAR Sjögren Syndrome Disease Activity Index, higher Sjögren Syndrome Disease Damage Index, and were more likely to have a positive parotid gland biopsy, anti-SSA/SSB antibodies, and abnormal unstimulated whole saliva (UWS) and ocular staining score (OSS), and higher levels of IgG and rheumatoid factor. Regarding patient-reported outcome measurements (PROM), patients who were SGUS positive scored significantly lower on the EULAR Sjögren Syndrome Patient-Reported Index for fatigue and pain, and more often found their disease state acceptable compared with patients who were SGUS negative. SGUS total score showed significant associations with various clinical and serological variables, and with PROM. Highest associations were found for UWS (ρ = –0.551) and OSS (ρ = 0.532).ConclusionPatients who were SGUS positive show a distinct clinical phenotype in all aspects of the disease compared with patients who were SGUS negative: clinical, functional, serological, and PROM. SGUS could be a helpful tool in selecting patients for clinical trials and estimating treatment need.

International audience; Objective. Juvenile Sjögren's syndrome (SS) is a rare, poorly defined, and possibly underdiagnosed condition affecting children and adolescents. The aim of this study was to characterize symptoms and clinical findings of juvenile SS and to explore the clinical application of major salivary gland ultrasonography (SGUS) in patients with juvenile SS. Methods. A cross-sectional multicenter study recruited patients with disease onset until age 18 years (n = 67). Disease characteristics were recorded, and unstimulated whole sialometry and SGUS examination of the parotid and submandibular salivary glands were performed. Results. The female:male ratio was 58:9. The mean age at first symptom was 10.2 years and 12.1 years at diagnosis. Ocular and oral symptoms were noted in 42 of 67 patients (63%) and 53 of 66 patients (80%), respectively. The American-European Consensus Group or American College of Rheumatology/European League Against Rheumatism classification criteria for primary SS were fulfilled by 42 of 67 patients (63%). Pathologic SGUS findings were observed in 41 of 67 patients (61%); 26 of 41 SGUS+ patients (63%) fulfilled primary SS criteria. Salivary gland enlargements/parotitis were noted in 37 of 58 patients and were nonsignificantly associated with SGUS+ status (P = 0.066). The mean levels of saliva were 5.6 ml/15 minutes in SGUS-patients compared to 3.3 ml/15 minutes in the SGUS+ patients (P = 0.049). A total of 36 of 41 SGUS+ patients (88%) were anti-Ro/La+ compared to 14 of 26 SGUS-patients (54%) (P = 0.001). In addition, 24 of 39 SGUS+ patients (62%) were positive for rheumatoid factor (RF), whereas only 5 of 25 SGUS-patients (20%) were RF+ (P = 0.001). Conclusion. Juvenile SS is characterized by a large spectrum of clinical symptoms and findings. Several glandular and extraglandular parameters such as hyposalivation, swollen salivary glands, and autoantibodies are associated with pathologic SGUS findings.

Objective The involvement of salivary glands in primary SS (pSS) can be assessed in different ways: histopathology, salivary flow and ultrasonography. To understand the relative value of these different approaches, it is crucial to understand the relationship between them. As we routinely perform these three modalities in the parotid gland for disease evaluation, our aim was to investigate the construct validity between these modalities in one and the same gland. Methods Consecutive sicca patients underwent a multidisciplinary diagnostic workup including parotid gland biopsy, collection of parotid gland–specific saliva and parotid gland ultrasonography. Patients who were classified as pSS according to the ACR-EULAR criteria were included. Construct validity was assessed using Spearman’s correlation coefficients. Results The 41 included pSS patients completed a full workup within a mean time interval of 2.6 months. Correlations between histopathological features and stimulated parotid salivary flow were fair (ρ = −0.123 for focus score and ρ = −0.259 for percentage of CD45+ infiltrate). Likewise, poor correlations were observed between stimulated parotid salivary flow and parotid ultrasonography (ρ = −0.196). Moderate to good associations were found between the histopathological items focus score and the percentage of CD45+ infiltrate, with parotid US scores (total US score: ρ = 0.510 and ρ = 0.560; highest for homogeneity: ρ = 0.574 and ρ = 0.633). Conclusion Although pSS-associated ultrasonographic findings did correlate with histopathological features, the three modalities that evaluate salivary gland involvement assess different (or at best partly related) constructs. Therefore histopathology, salivary flow and ultrasonography are complementary measurements and cannot directly replace each other in the workup of pSS.

Primary Sjögren’s syndrome is a chronic, systemic auto-immune disease characterized by inflammation of the lacrimal and salivary glands. This thesis demonstrates that major salivary gland ultrasonography is a promising non-invasive method to investigate salivary gland involvement in (suspected) Sjögren’s patients. Major salivary gland ultrasonography is able to predict the outcome of a salivary gland biopsy at group level, but it cannot fully replace the biopsy for each individual patient. The combination of a positive ultrasound and the presence of anti-SSA antibodies (in blood) predicts very well if a patient will be classified with Sjögren’s syndrome. For diagnostic purposes, it suffices to use a compact ultrasound scoring system, while for the division of classified Sjögren’s patients in subgroups, a more comprehensive scoring system is warranted. With the addition of salivary gland ultrasonography to the classification criteria for Sjögren’s syndrome, the accuracy is comparable. However, the feasibility increases since clinicians are able to choose from a wider array of tests. A detailed analyses was performed between three different methods that assess the involvement of the parotid gland, that is a biopsy, collection of saliva and ultrasonography. All three methods provide other (unique) information and are therefore complementary to each other. Finally, the efficacy and safety of treatment with abatacept has been investigated.

Objective: To investigate treatment efficacy of long-term abatacept treatment in pSS patients.Methods: The single-centre ASAP-III trial consisted of two phases: the randomised, double-blind, placebo-controlled phase (1:1 randomisation) from baseline to week 24, of which results have been published previously, and the open-label extension phase from week 24 to 48, in which all patients received abatacept. Main inclusion criteria were fulfilment of the AECG criteria, positive gland biopsy, disease duration = 5. Long-term treatment effects of abatacept on clinical, patient-reported, glandular and laboratory outcome measures were assessed in patients treated with abatacept from baseline to week 48. Furthermore, Composite of Relevant Endpoints for Sj_ogren's Syndrome (CRESS) response (response on >= 3 of 5 items) was analysed.Results: In patients on abatacept treatment for 48 weeks (n = 40), median ESSDAI improved from baseline 14.0 (IQR 9.0 - 16.8) to 4.0 (2.0 - 8.0) at week 48 (p < 0.001), with 50% of patients reaching low disease activity (ESSDAI < 5) at week 48. Median ESSPRI improved from 7.0 (IQR 5.4-7.7) to 5.0 (3.7-6.7) (p < 0.001). Significant improvement was also seen in dry eye and laboratory tests. Combining response at multiple clinically relevant items, 73% of patients were CRESS responders at week 48. Additional improvement was seen between week 24 and week 48 of abatacept treatment.Conclusion: In the open-label extension phase of the ASAP-III trial, improvement was seen up to 48 weeks of abatacept treatment in clinical, patient-reported, dry eye and laboratory outcomes. The majority of patients were CRESS responders at week 48. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Within the last year, interesting developments regarding the assessment of salivary gland involvement in patients with clinical suspicion of, or diagnosed with primary Sjögren's syndrome (pSS) have been performed. In this review various topics will be discussed, starting with the use of salivary gland ultrasonography (SGUS) for the detection of glandular swelling. Furthermore, other imaging modalities, besides B-mode SGUS, which differentiate between pSS patients and healthy controls will be highlighted. Moreover, storage of ultrasonographic images and videos will be discussed briefly, as will be some potential biases and pitfalls. Finally, efforts that have been made to make incorporation of SGUS into the most recent classification criteria possible will be discussed, as well as the important steps that have been taken to develop a new semi-quantitative scoring system for the assessment of salivary gland involvement in patients with suspected or confirmed pSS.

To evaluate the presence of sicca symptoms and secondary Sjögren's syndrome (SS) and the association with clinical characteristics, functional tests and patient-reported outcomes in patients with rheumatoid arthritis (RA) at baseline and after 10 years of follow-up.A cohort of RA patients was evaluated in 2008 and re-evaluated in 2018 with respect to sicca symptoms, presence of secondary SS according to AECG classification criteria, disease activity of RA and patient-reported outcomes. Patient characteristics were compared between the RA-non-sicca, RA-sicca and RA-SS groups.Of the original 2008 cohort of 96 RA patients, 32 (33%) had sicca symptoms and 6 (6.3%) secondary SS. Of the 36 patients who agreed to be re-evaluated in 2018, 6 (17%) had sicca symptoms and 2 (6%) developed secondary SS. In the majority of patients, sicca symptoms were reversible while the functional tests of salivary and lacrimal glands significantly decreased. 67% of RA-sicca patients had no sicca complaints at the second screening, while only two RA-sicca patients developed secondary SS. RA-SS patients and, to a slightly lesser extent, RA-sicca patients had significantly higher RA disease activity (DAS-28), lower lacrimal (Schirmer's test) and salivary gland function, more limitations in daily activities (HAQ), worse health-related quality of life (RAND-36), more fatigue (MFI) and more patient symptoms (ESSPRI) compared to RA-non-sicca patients.Secondary SS was found in a minor subset of the RA patients. Sicca symptoms of the eyes or mouth were more frequent, but their presence varied over time. Higher RA disease activity was associated with SS and sicca symptoms. These patients had lower gland function and worse patient-reported outcomes.

Objectives. Serum immunoglobulin free light chains (FLCs) are frequently elevated in B-cell-mediated autoimmune diseases, including primary SS (pSS). The objective of this study was to assess if serum FLCs can contribute to classification, mucosa-associated lymphoid tissue (MALT) lymphoma detection, monitoring of disease activity and treatment response in pSS.Methods. Serum samples of 100 consecutive patients suspected of pSS were included. Forty-five patients fulfilled ACR-EULAR criteria for pSS. Additionally, samples of 17 pSS patients with MALT lymphoma and longitudinal samples of pSS patients treated with rituximab (n = 20), placebo (n = 10) or abatacept (n = 15) were included. Serum FLC kappa/FLC lambda. was measured by nephelometry or turbidimetry.Results. At diagnosis, FLC kappa and FLC lambda serum levels were significantly higher in pSS compared with non-SS sicca patients. The FLC kappa/FLC lambda ratio was abnormal in 11% of pSS patients. In established MALT-pSS patients, without recent rituximab treatment (n = 12), 50% had abnormal FLC kappa/FLC lambda ratios. FLC measurement had no additional value for pSS classification, compared with IgG and anti-SSA. FLC levels correlated significantly with systemic disease activity, assessed by EULAR SS Disease Activity Index (ESSDAI) and clinical ESSDAI, both cross-sectionally and longitudinally following treatment. Treatment with rituximab or abatacept significantly lowered FLC levels. FLCs show a large sensitivity to change and relative changes induced by treatment were higher compared with IgG.Conclusion. Serum FLCs are elevated in pSS, and abnormal FLC kappa/FLC lambda. ratios may be indicative for the presence of MALT lymhoma. FLC levels can be used as a biomarker for systemic disease activity and monitoring treatment responses. FLCs are sensitive to change and have more favorable kinetics than IgG.

ObjectiveTo assess the validity of ultrasound of major salivary glands (sUS) compared with parotid and labial gland biopsies, sialometry, anti-SSA/Ro antibody status and classification criteria in patients clinically suspected with primary Sjögren’s syndrome (pSS).Methods103 consecutive outpatients with clinically suspected pSS underwent sUS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and clearness of salivary gland border were scored according to the Hocevar scoring system. Total ultrasound score was calculated as the sum of these domains (range 0–48).ResultsAbsolute agreement between sUS and parotid (83%) and labial (79%) gland biopsy outcome was good. Negative sUS predicts negative parotid gland biopsy, and positive sUS predicts positive labial gland biopsy. Compared with the American European Consensus Group (AECG) classification, sUS showed an absolute agreement of 82%, sensitivity of 71% and specificity of 92%. Compared with the American College of Rheumatology (ACR) classification, absolute agreement was 86%, sensitivity was 77% and specificity was 92%. Compared with the ACR-European League Against Rheumatism (EULAR) classification, absolute agreement was 80%, sensitivity was 67% and specificity was 94%. Positive sUS predicts classification, but negative sUS does not exclude classification. The combination of positive sUS with presence of anti-SSA/Ro antibodies or negative sUS with absence of anti-SSA/Ro antibodies showed a high predictive value for classification as pSS or non-pSS.ConclusionIn our prospective inception cohort study derived from daily clinical practice, absolute agreement between sUS and salivary gland biopsies was slightly higher for parotid compared with labial gland biopsies. The combination of positive sUS and presence of anti-SSA/Ro antibodies highly predicts classification according to the AECG, ACR and ACR-EULAR classification criteria.

Background Effective systemic treatment is not yet available for primary Sjogren syndrome (pSS). Abatacept (CTLA-4-Ig) targets the CD80/CD86:CD28 co-stimulatory pathway required for full T-cell activation and T-cell dependent activation of B-cells. IV abatacept was shown to be safe, well tolerated, and to decrease disease activity in an open-label study of 15 pSS patients.1 Objectives To assess the efficacy and safety of subcutaneous (SC) abatacept vs. placebo in patients with early active pSS. Methods The Abatacept Sjogren Active Patients phase III (ASAP-III) study is a monocenter, investigator-initiated, double-blind, placebo-controlled trial (NCT02067910). ASAP-III included 80 adult patients with biopsy-proven pSS, fulfilling the AECG and ACR/EULAR criteria, with a disease duration of ≤7 years and moderate to high EULAR Sjogren’s syndrome disease activity score (ESSDAI ≥5). Patients were randomized in a 1:1 ratio to receive weekly SC abatacept (125 mg) or placebo for 24 weeks (figure 1). After the double-blind phase, all patients were treated with abatacept in a 24-week open label phase. Concomitant use of other DMARDs was not permitted, with the exception of a stable dose of prednisone (≤10mg). Rescue therapy with prednisone or cyclophosphamide was permitted after week 12. Participants visited our pSS tertiary referral center nine times, to be evaluated by a multidisciplinary team of rheumatologists, ophthalmologists, and oral and maxillofacial surgeons. The primary endpoint is ESSDAI at 24 weeks. Secondary outcomes over 24 and 48 weeks include clinical, patient reported, functional, histological, laboratory, ultrasound, and microbiome parameters, and the occurrence of (serious) adverse events and treatment discontinuation. Results Baseline characteristics of participants are shown in table 1. Database lock for the blinded stage is planned in March 2019. Subsequently, the first intention-to-treat analyses will be performed, focusing on the ESSDAI and EULAR Sjogren Syndrome Patient Reported Index (ESSPRI), quality of life (EQ-5D), unstimulated and stimulated whole salivary flow (UWS, SWS), Schirmer test, Ocular Staining Score (OSS), serological parameters (RF, IgG), and safety parameters. Conclusion The ASAP-III trial was designed to assess the clinical efficacy and safety of SC abatacept in pSS patients with short disease duration and active disease. The 24-week results will be available during the EULAR congress 2019. Reference [1] Meiners, et al. Ann Rheum Dis2014;73:1393-6. Disclosure of Interests Jolien F. van Nimwegen Speakers bureau: Bristol-Myers Squibb, Greetje S. van Zuiden Speakers bureau: Roche, Suzanne Arends Grant/research support from: Grant/research support from Pfizer, Esther Mossel: None declared, Robin F. Wijnsma: None declared, Alja J. Stel: None declared, Konstantina Delli: None declared, Bert van der Vegt: None declared, Erlin A. Haacke: None declared, Lisette Olie: None declared, Leonie I. Los: None declared, Janita Bulthuis-Kuiper: None declared, Gwenny M. Verstappen: None declared, Sarah A. Pringle: None declared, Fred K.L. Spijkervet: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Roche, Janssen-Cilag, Arjan Vissink: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant for: Roche, Bristol-Myers Squibb, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Bristol-Myers Squibb, Novartis

With great interest we have read the recent publication by Fisher et al ,1 entitled ‘Effect of rituximab on a salivary gland ultrasound score in primary Sjogren’s syndrome: results of the TRACTISS randomised double-blind multicenter substudy’ in which the authors demonstrated a significant improvement in total ultrasound score (TUS) after rituximab treatment compared with placebo at weeks 16 and 48 in 52 patients with primary Sjogren’s syndrome (pSS). We and others have shown that treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, affects the histopathology of the salivary glands and results in a decrease in area of lymphocytic infiltrate in the labial and parotid glands.2–5 This reduction in infiltrated area, that is, up to 50%, is mainly caused by B cell depletion.2 Rituximab treatment also causes a significant loss of germinal centres.2 Interestingly, rituximab treatment also leads to a significant restoration of the ductal epithelium glandular tissue itself. This is illustrated by a significant decrease in number and severity of lymphoepithelial lesions (LELs) in parotid gland tissue 12 weeks after rituximab treatment.2 6 The normalisation of the epithelium appears to be a direct consequence of depletion of intraepithelial B cells.7 Significant improvement of the parotid gland ultrasound score of patients with pSS has been observed before in another randomised controlled trial (RCT) with rituximab, the Tolerance and Efficacy of Rituximab in Primary Sjogren’s Syndrome (TEARS) study.8 This is an RCT with rituximab versus placebo, performed by a French group. Together with the improvement of the histopathology of the gland, it might not be a surprise that Fisher et al 1 also observed a significant improvement in TUS. This newly …

Objective: To assess whether the addition of salivary gland ultrasonography (SGUS) or replacement of current criteria items by SGUS influences the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for primary Sjögren's syndrome. Methods: Included were consecutive patients with complete data on all ACR/EULAR items (n = 243) who underwent SGUS in our primary Sjögren's syndrome expertise center. Clinical diagnosis by the treating physician was used as the gold standard. Separate analyses were performed for patients who underwent labial or parotid gland biopsies. The average score for hypoechogenic areas in 1 parotid and 1 submandibular gland was determined (range 0–3). Next, performance of the ACR/EULAR criteria was evaluated after addition of SGUS or replacement of current items by SGUS. Results: Receiver operating characteristic analysis showed an optimal cutoff value of ≥1.5 for SGUS. The optimal weight for SGUS positivity was 1. Cutoff for ACR/EULAR fulfilment remained ≥4. In patients who underwent a labial gland biopsy (n = 124), the original criteria showed an area under the curve (AUC) of 0.965, sensitivity of 95.9%, and specificity of 92.2%. After the addition of SGUS, the AUC was 0.966, with a sensitivity of 97.3% and specificity of 90.2%. In patients who underwent a parotid gland biopsy (n = 198), similar results were found. Sensitivity of the criteria decreased substantially when SGUS replaced salivary gland biopsy or anti-SSA antibodies, while performance remained equal when SGUS replaced the ocular staining score, Schirmer's test, or unstimulated whole saliva flow. Conclusion: Validity of the ACR/EULAR criteria remains high after incorporation of SGUS. With SGUS, clinicians are offered a larger array of tests to evaluate fulfillment of the ACR/EULAR criteria.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dysfunction and lymphocytic infiltration of the salivary and lacrimal glands. Besides the characteristic sicca complaints, pSS patients can present a spectrum of signs and symptoms, which challenges the diagnostic process. Various imaging techniques can be used to assist in the diagnostic work-up and follow-up of pSS patients. Developments in imaging techniques provide new opportunities and perspectives. In this descriptive review, we discuss imaging techniques that are used in pSS with a focus on the salivary glands. The emphasis is on the contribution of these techniques to the diagnosis of pSS, their potential in assessing disease activity and disease progression in pSS, and their contribution to diagnosing and staging of pSS-associated lymphomas. Imaging findings of the salivary glands will be linked to histopathological changes in the salivary glands of pSS patients.

Background:Abatacept (CTLA-4-Ig) targets the CD80/CD86:CD28 co-stimulatory pathway required for full T-cell activation and T-cell dependent activation of B-cells. The Abatacept Sjögren Active Patients phase III (ASAPIII) trial is a mono-center, investigator-initiated, placebo controlled study with an open-label extension phase (NCT02067910), which assessed the efficacy and safety of weekly subcutaneous abatacept (125mg) in patients with early active primary Sjögren’s syndrome (pSS). Previous analyses of the double blind phase showed no significant effect of abatacept treatment compared to placebo on the primary endpoint, difference in EULAR Sjögren’s syndrome disease activity index (ESSDAI) at week 24.1Objectives:To evaluate the efficacy and safety of extended (48 weeks) open label abatacept treatment in pSS patients.Methods:Included patients had biopsy-proven pSS, fulfilled the AECG and ACR-EULAR criteria, had disease duration ≤7 years (median 2 years), ESSDAI ≥5, and 89% were anti–SSA positive. All 40 patients who received abatacept (ABA) in week 0-24 were subsequently treated with abatacept from week 24-48. Of the 40 patients who received placebo (PLB) in week 0-24, 2 were lost to follow up, and 38 were treated with abatacept from week 24-48. Systemic disease activity (ESSDAI), patient reported symptoms (ESSPRI), serological outcomes (RF and IgG), ocular staining score (OSS) and unstimulated whole salivary flow (UWS) were assessed. We evaluated whether outcomes improved within treatment groups, from week 0 to subsequent visits and from week 24 to subsequent visits:1.Within ABA→ABA treated patients:a. Week 0-48 to assess overall efficacy.b. Week 24-48 to assess additional efficacy of long term treatment.2.Within PLB→ABA treated patients:a. Week 0-24 to assess whether a placebo effect occurred.b. Week 24-48 to assess short-term efficacy of open label ABA.GEE modeling was used to test significance of changes over time. Missing data were not imputed.Results:ESSDAI and ESSPRI were improved within ABA/ABA patients between week 0-48 with additional efficacy after week 24, and within PLB/ABA patients after switching to ABA. Significant decreases in ESSDAI and ESSPRI were also seen within PLB treated patients between week 0-24 (Figure 1). IgG and RF were improved within ABA/ABA patients between week 0-48 with additional efficacy after week 24, and within PLB/ABA patients after switching to ABA. OSS was improved within ABA/ABA treated patients between week 0-48. UWS only showed significant improvement in week 36 within ABA/ABA treated patients. No changes in IgG, RF, OSS or UWS were seen within PLB treated patients. No deaths occurred. One serious adverse event possibly related to intervention occurred during ABA treatment.Conclusion:ESSDAI and ESSPRI improved significantly during 48-week treatment with abatacept. Placebo treated patients also showed significant improvement in both indices and further improvement occurred after switching to abatacept. Biological activity was decreased by abatacept treatment. 48-week abatacept treatment improved OSS, and might improve UWS. Abatacept was well tolerated by pSS patients.References:[1]van Nimwegen et al. Lancet Rheumatol.Published online 31-01-2020Acknowledgments:This study was funded by Bristol-Myers Squibb. We thank all patients for participation in the ASAP-III trial.Disclosure of Interests:Suzanne Arends Grant/research support from: Grant/research support from Pfizer, Jolien F. van Nimwegen Consultant of: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Esther Mossel: None declared, Greetje S. van Zuiden Speakers bureau: Roche, Konstantina Delli: None declared, Alja J. Stel: None declared, Bert van der Vegt Consultant of: Advisory board member for Philips and Visiopharm., Erlin A. Haacke: None declared, Lisette Olie: None declared, Leoni Los: None declared, Gwenny M. Verstappen: None declared, Sarah A. Pringle: None declared, Fred K.L. Spijkervet: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant of: Consultant for Bristol-Myers Squibb, Speakers bureau: Speaker for Bristol-Myers Squibb, Roche and Janssen-Cilag, Arjan Vissink: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant of: Consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Speaker for Bristol-Myers Squibb and Novartis.

Background Salivary gland ultrasound (SGUS) is cheap, non-invasive and easy to perform in an outpatient setting. The ACR-EULAR criteria were recently developed to reach international consensus regarding the classification of primary Sjogren’s syndrome (pSS), but SGUS is not yet included as a classification item. Objectives To assess the performance of the ACR-EULAR criteria when salivary gland ultrasound (SGUS) replaces current items, in a large cohort of patients clinically suspected or diagnosed with pSS in daily clinical practice. Methods Included were all consecutive outpatients who underwent SGUS between October 2014 and , July 2017 and had a complete data-set on all ACR-EULAR items. Classification according to the criteria was determined separately in patients who were subjected to a labial or parotid gland biopsy. For SGUS, the average score for hypoechogenic areas in the parotid and submandibular glands on one side was applied (range 0–3)1. The optimal cut-off value for our SGUS score was determined using ROC analysis. Clinical diagnosis by the treating physician was used as gold standard. Area under the curve (AUC), absolute agreement, sensitivity and specificity of the original and adjusted ACR-EULAR criteria sets were determined. Results Of the 363 consecutive patients, 243 patients had a complete data-set, of whom 147 patients were diagnosed with pSS. Accuracy of SGUS to predict clinical diagnosis was good, with an AUC of 0.860 and optimal cut-off value of ≥1.5. When applying a weight of 1 point for a positive SGUS, the cut-off value of the ACR-EULAR criteria to discriminate between pSS and non-pSS remained 4, irrespective of the type of biopsy used. In patients who underwent a labial gland biopsy (n=124), the original ACR-EULAR criteria showed an AUC of 0.965 (figure 1A). Absolute agreement with clinical diagnosis was 94.4%, sensitivity was 95.9% and specificity was 92.2%. When SGUS replaced the labial gland biopsy, absolute agreement was 87.9%, sensitivity was 82.2% and specificity was 96.1%. When SGUS replaced anti-SSA antibody status, absolute agreement was 89.5%, sensitivity was 86.3% and specificity was 94.1%. When SGUS replaced the ocular staining score (OSS), Schirmer’s test or unstimulated whole saliva flow (UWS), absolute agreement varied between 89.5%–93.5%, sensitivity varied between 90.4%–95.9% and specificity varied between 88.2%–92.2%. In patients who underwent a parotid gland biopsy (n=198), similar results were found (figure 1B). Conclusions SGUS cannot be used as a replacement for salivary gland biopsy or anti-SSA antibody status in the ACR-EULAR criteria because of a substantial reduction in sensitivity. For diagnostic purposes, a high sensitivity is preferred over a high specificity. Replacement of the OSS, Schirmer’s test or UWS by SGUS only resulted in negligible changes in accuracy of the ACR-EULAR criteria. With SGUS being able to replace one of these function tests, clinicians are offered more options that could lead to fulfilment of the ACR-EULAR criteria. Reference [1] Mossel, et al. Ann Rheum Dis2017: Published online first at December 12. Disclosure of Interest None declared

ObjectiveTo assess whether ultrasonographic scoring of (i) both parotid and submandibular salivary glands and (ii) all individual components of the Hocevar scoring system, is needed for classifying patients as primary Sjögren’s syndrome (pSS).MethodsUltrasound examination of the major salivary glands (sUS) was performed in 204 consecutive patients clinically suspected (n=171) or diagnosed (n=33) with pSS.Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and salivary gland posterior border were scored in left and right parotid and submandibular glands. Logistic regression analyses were performed to assess which glands and sUS components contributed significantly to classification as pSS or non-pSS according to the 2016 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) criteria.Results116 (57%) patients were classified as pSS, the remaining as non-pSS. Instead of scoring both sides (area under the curve; AUC=0.856, Nagelkerke R2=0.526), multivariate analysis showed that sUS scoring of only right (AUC=0.850; R2=0.518) or left (AUC=0.852; R2=0.511) parotid and submandibular glands is sufficient to predict ACR-EULAR classification. Moreover, all individual components of the Hocevar scoring system significantly predicted classification. Multivariate analysis showed that parenchymal echogenicity and hypoechogenic areas contributed independently to ACR-EULAR classification (AUC=0.857; R2=0.539). Scoring these components in one parotid and one submandibular gland highly predicted ACR-EULAR classification (AUC=0.855; R2=0.539). Scoring only hypoechogenic areas on one side showed almost similar results (AUC=0.846; R2=0.498).ConclusionsUS examination of parotid and submandibular glands on one side is sufficient to predict classification of patients according to the ACR-EULAR criteria. To further increase feasibility of sUS in outpatient clinics worldwide, only hypoechogenic areas can be scored.

Background Juvenile Sjogren9s syndrome (jSS) is a rare, poorly defined and possibly underdiagnosed condition. There is little information on the use of major salivary gland ultrasonography (SGUS) in this patient-group. Objectives To characterize symptoms and clinical findings of jSS and to investigate SGUS as a diagnostic tool. Methods Sixty-four patients were recruited from Brazil (n=40), Norway (n=11), the Netherlands (n=8) and Spain (n=5). All patients had disease onset at the age of 18 or younger. Clinical examination and sialometry was performed in 60/64 patients. Additional clinical information was obtained from the medical records and through patient interview. SGUS of the parotid and submandibular glands was performed in all patients using linear high-frequency transducers (6–15 MHz), by an expert in SGUS. Glandular homogeneity and presence of hypoechogenic areas were evaluated and glands characterized as normal or SS-like. Results The female:male ratio was 6:1. Mean age at diagnosis was 12.1 years (range 4–18), with first symptoms occurring at 10.3 years (range 1–17). Time from onset of symptoms until diagnosis was 1.6 years (range -2–8 years). Subjective oral and ocular symptoms were reported in 70% and 64% patients, respectively. Reduced secretion of tears was detected in 41% patients, and hyposalivation in 31% patients. Minor salivary gland lip biopsy had been performed and focus score determined in 34 patients; 28 biopsies (82%) had focus score ≥1. Serologically, 92% were positive for ANA, 73% were anti-Ro/SSA+, 38% were anti-La/SSB+, and 41% were RF+. Salivary gland enlargement had been experienced by 53% of the patients; one patient had also experienced lacrimal gland enlargement. Systemic manifestations at some time-point, was registered in 66% of the patients. Systemic treatment at inclusion was registered in 67% of the patients; previous systemic treatment was registered in 83%. Diagnostic criteria for primary Sjogren9s syndrome (pSS) was fulfilled by 34/64 patients (53%) and 39/64 patients (61%), AECG criteria and ACR/EULAR criteria, respectively. SGUS revealed SS-like changes in 37/64 patients (59%); interestingly, SS-like findings were observed in 22/23 patients in the European cohort, compared to 15/40 patients in the Brazilian cohort. Conclusions Common symptoms and findings in jSS include dry mouth, systemic manifestations and salivary gland enlargement, followed by reduced tear secretion and hyposalivation. Disclosure of Interest None declared

We read with great interest the article by Fonseca et al (1), that was published in a recent issue of Arthritis & Rheumatology. The authors elegantly showed that T follicular regulatory (Tfr) cells were enriched in blood as well as in matched minor salivary gland (MSG) biopsies from patients with primary Sjögren's syndrome (pSS). They also showed that the Tfr/Tfh ratio in blood was increased in pSS compared to non-SS sicca patients. Interestingly, this Tfr/Tfh ratio in blood correlated with ectopic lymphoid structure formation in MSG tissue. To our opinion the authors did, however, not show a direct correlation between aberrant Tfr/Tfh ratios and ectopic lymphoid structure formation among pSS patients. In essence their study showed that in pSS patients the Tfr/Tfh ratio in blood was correlated with numbers of infiltrating lymphocytes, as assessed by flow cytometric analysis of MSG cell suspensions. Additionally, the authors showed that the Tfr/Tfh ratio in blood was increased in patients with focal sialoadenitis (FSA) (defined in their study as a focus score ≥1), compared to patients without FSA. Of note, this comparison was made irrespective of a diagnosis of pSS, which implicated that the majority of patients without FSA were non-SS sicca patients. This article is protected by copyright. All rights reserved.

Objectives: The parotid glands are commonly involved in primary Sjogren syndrome (pSS). The aim of this study was to assess the diagnostic accuracy of ultrasound of the parotid glands (PSGUS) compared with parotid histopathology and parotid saliva production. Study Design: We included consecutive patients suspected to have pSS. All patients underwent a full diagnostic workup according to American College of Rheumatology– European League Against Rheumatism (ACR-EULAR) criteria, including PSGUS, parotid gland biopsy, and collection of stimulated parotid saliva. For PSGUS, the average score of hypoechogenic areas in both parotid glands was applied (range 0-3). On hematoxylin and eosin (HE P < .001) and percentage of lymphocytic infiltrate (ρ = 0.575; P < .001). There was a moderate to good absolute agreement between the PSGUS and focus scores (78.5%), plasma cell shift (79.8%), LELs (81.4%), and GCs (82.7%). “Presence of hypoechogenic areas” was not very sensitive to predict focus score (69.2%), plasma cell shift (45.8%), LELs (61.5%), or GCs (34.6%). Interestingly, almost all patients with less than 25% presence of hypoechogenic areas in glandular parenchyma were also negative for GCs (98.7%). A substantial number of these patients did not have a positive focus score (81.4%), plasma cell shift (90.7%), or LELs (87.8%). There was a fair reversed correlation between PSGUS and stimulated parotid saliva flow (ρ = −0.259; P = .07). Conclusions: This is the first study comparing the diagnostic accuracy of PSGUS with histopathology and salivary secretion in detail. PSGUS and histopathology have a stronger association compared with PSGUS and parotid secretion. The specificity of PSGUS increases when the results are compared with plasma cell shift, LELs, and GCs, rather than with the focus score.

We would like to thank Alegria et al 1 for their letter to the editor commenting on our recent publication entitled ‘Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjogren’s syndrome’.2 Our study was the first that directly compared the validity of ultrasound of major salivary glands (sUS) with parotid gland biopsy outcome. We showed that the agreement between sUS and parotid as well as labial gland biopsies was good but was slightly higher for the former. As noted by Alegria et al ,1 we found different results for the positive predictive value (PPV) and negative predictive value (NPV) between sUS versus parotid and sUS versus labial gland biopsies.2 Although these observations may indeed be caused by discordance between the parotid and labial gland biopsy outcome, there are other factors that may equally well contribute to this discrepancy. First, the parotid glands are assessed during the sUS examination and included in the scoring, whereas the labial glands are not.2 Second, in 6%–15% of the general population, the labial gland biopsy is positive, while in only 5% of the general population, the parotid gland biopsy is positive. …

Background Ultrasound of major salivary glands (sUS) is an upcoming diagnostic method to assess the involvement of major salivary glands in primary Sjogren9s syndrome (pSS). In the AECG, ACR and recently published ACR-EULAR criteria, a positive salivary gland biopsy and/or presence of anti-SSA antibodies are necessary to classify a patient as pSS, while sUS is not included as a diagnostic item. Objectives To assess whether combining anti-SSA antibody status with sUS outcome can predict classification of patients as pSS in our inception cohort study. Methods Consecutive outpatients clinically suspected with pSS underwent sUS of the parotid and submandibular glands. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and clearness of salivary gland border were scored according to the Hocevar scoring system (total score 0–48). 1 Positive sUS was defined as total score ≥15. Patients underwent a diagnostic work up according to the AECG, ACR and ACR-EULAR criteria. We analyzed the predictive value of the combination of anti-SSA antibody status and sUS outcome for classification as pSS or non-pSS. Separate analyses were done considering either i) parotid gland biopsy or ii) labial gland biopsy as an item, when applying these classification criteria. Results Anti-SSA antibody status was positive in 53 (51%) patients and sUS was positive in 40 (39%) patients. When parotid gland biopsy outcome was considered as an item of the criteria, 45 of 97 patients were classified as pSS according to the AECG, 44 of 97 according to the ACR and 52 of 99 according to the ACR-EULAR criteria. The combination of presence of anti-SSA antibodies with positive sUS showed a very high positive predictive value for classification as pSS (94–97%) and the combination of absence of anti-SSA antibodies with negative sUS highly excludes classification (negative predictive value 98–100%). When labial gland biopsy outcome was considered as an item of the criteria, 49 of 96 patients were classified as pSS according to the AECG, 43 of 93 according to the ACR and 55 of 97 according to the ACR-EULAR criteria. The combination of presence of anti-SSA antibodies with positive sUS showed a high positive predictive value for classification as pSS (94–97%). However, the combination of absence of anti-SSA antibodies with negative sUS did not per se exclude classification (negative predictive value 89–93%). Conclusions In our prospective inception cohort study derived from daily clinical practice, the combination of presence of anti-SSA antibodies and positive sUS outcome highly predicts classification as pSS according to the AECG, ACR and ACR-EULAR classification criteria. References Hocevar et al. Rheumatology (Oxford) 2005;44:768–72. Disclosure of Interest None declared

ObjectiveTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR).MethodsTo develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed.ResultsThe Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance.ConclusionThe candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.