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Summary Background Recent randomised controlled trials (RCTs) in primary Sjogren's syndrome used the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjogren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjogren's syndrome: the Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS). Methods A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders. Findings Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjogren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p Interpretation The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjogren's syndrome. As a next step, the CRESS will require validation in a prospective RCT. Funding None. Translation For the Dutch translation of the abstract see Supplementary Materials section.

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).

Vaginal dryness is a common yet under-recognized symptom in women with Sjögren’s disease. It is not currently known whether inflammation in the vaginal and endocervical mucosa causes this localized dryness. Vaginal dryness is associated with increased rates of discomfort during daily living as well as an increased risk for pain that occurs during sexual intercourse (dyspareunia). The overall composition of the vaginal microbiome of Sjögren’s patients is similar to that of patients without Sjögren’s. Vaginal dryness can be managed with the use of currently available treatments, including water-soluble lubricating products, probiotic and hyaluronic acid moisturizers, estrogen creams, and estradiol-based vaginal inserts.

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.

Objective The aim was to study clinical, histopathological and immunological changes in the vagina and cervix of women with primary SS, which might explain vaginal dryness. Methods We included 10 pre-menopausal female primary SS patients with vaginal dryness and 10 pre-menopausal controls undergoing a laparoscopic procedure. The vaginal health index was recorded. Multiplex immunoassays and flow cytometry were performed on endocervical swab and cervicovaginal lavage samples to evaluate cellular and soluble immune markers. Mid-vaginal and endocervical biopsies were taken and stained for various leucocyte markers, caldesmon (smooth muscle cells), avian V-ets erythroblastosis virus E26 oncogene homologue (ERG; endothelial cells) and anti-podoplanin (lymphatic endothelium). The number of positive pixels per square micrometre was calculated. Results One patient was excluded because of Clamydia trachomatis, and two controls were excluded because of endometriosis observed during their laparoscopy. Vaginal health was impaired in primary SS. CD45+ cells were increased in vaginal biopsies of women with primary SS compared with controls. Infiltrates were predominantly located in the peri-epithelial region, and mostly consisted of CD3+ lymphocytes. In the endocervix, CD45+ infiltrates were present in patients and in controls, but a higher number of B lymphocytes was seen in primary SS. Vascular smooth muscle cells were decreased in the vagina of primary SS patients. No differences were found in leucocyte subsets in the vaginal and endocervical lumen. CXCL10 was increased in endocervical swab samples of primary SS patients. Conclusion Women with primary SS show impaired vaginal health and increased lymphocytic infiltration in the vagina compared with controls. Vaginal dryness in primary SS might be caused by vascular dysfunction, possibly induced by IFN-mediated pathways.

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.

The majority of women with primary Sjögren's syndrome (pSS) suffer from vaginal dryness, which negatively impacts daily and sexual activities. As little is known about the aetiology and clinical context of this complaint, this study investigated the relationship between vaginal dryness and other clinical parameters associated with pSS.Female participants of the REgistry of Sjögren syndrome at UMCG - LongiTudinal (RESULT) cohort who fulfilled ACR-EULAR and/or AECG classification criteria for pSS were included, using baseline data for analyses. Patient-reported vaginal dryness (range 0-10) was correlated with demographic characteristics, systemic disease activity (i.e., ESSDAI), Sjögren's Syndrome Disease Damage Index, salivary and lacrimal gland function, patient-reported outcomes (ESSPRI, MFI), serology and quality of life (SF-36, EQ-5D). Significantly associated parameters (p0.05) were corrected for potential confounders.This cross-sectional study included 199 women with pSS; mean age was 52±14 years, 53% were postmenopausal, and median vaginal dryness score was 5 (IQR 2-7). Vaginal dryness was significantly associated with older age, postmenopausal status, peripheral neuropathy, oral and ocular dryness, ESSPRI and SF-36 mental and general health. After correction for age, menopausal status and medication use, peripheral neuropathy (B=1.632), oral dryness (B=0.302), and ocular dryness (B=0.230) were independently associated with vaginal dryness.The independent association of vaginal dryness with oral and ocular dryness might imply that the aetiology of these symptoms is partly shared. Of all extraglandular features, only peripheral neuropathy was independently associated with vaginal dryness, suggesting that peripheral neuropathy plays a significant role in the pathology of vaginal dryness in pSS.

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/)

Primary Sjögren's syndrome (pSS) is a very heterogeneous disease with systemic manifestations such as arthritis, skin, lung and renal involvement. To be able to assess systemic disease activity, the EULAR Sjögren's syndrome disease activity index (ESSDAI) was developed for use in daily clinical practice and in clinical trials. Since its development it has been widely used in cohort studies and clinical trials. The ESSDAI gives a systematic overview of a patient's systemic disease activity, which is very useful in daily clinical practice. However, using the ESSDAI as outcome measure in trials has been more challenging. Several RCTs with the ESSDAI as primary endpoint failed and showed large 'response rates' in placebo-treated patients as well. In this review, we discuss what we learned from using the ESSDAI in cohorts and clinical trials. We recommend to use the ESSDAI only in combination with other important outcome measures, such as patient-reported symptoms and glandular function as part of a composite endpoint in clinical trials in pSS patients.

Primary Sjögren’s syndrome (pSS) is a systemic auto-immune disease. Important symptoms of pSS include dryness of the eyes, mouth, and vagina, fatigue, and pain. This thesis focuses on the impact of pSS on sexual function, classification of pSS and treatment of pSS. The first part of the thesis shows that women with pSS experience a worse sexual function compared to healthy women. In the vagina of pSS patients, the number of white blood cells is increased, indicating the presence of a chronic inflammatory process. Furthermore, the number of smooth muscle cells around blood vessels in the vagina of patients is decreased, which may disturb the production of fluid in the vagina. The new ACR-EULAR classification criteria were designed to classify patients with pSS for inclusion in clinical studies. This thesis shows that the ACR-EULAR criteria can accurately distinguish patients with and without pSS and remain accurate when salivary gland ultrasonography is added to the criteria. Patients with abnormalities on salivary gland ultrasonography show higher disease activity and worse salivary and tear gland function. The final part of the thesis evaluated the efficacy and safety of new treatments for pSS. A randomised controlled trial showed that treatment with abatacept does not decrease systemic disease activity in pSS patients in general. However, additional analyses should be performed to assess whether abatacept is effective in certain subgroups of pSS patients. A review of literature shows that rituximab is also not effective in all pSS patients, but selected patients may benefit from this treatment.

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.

Objectives. To validate the ACR-EULAR classification criteria for primary SS (pSS), and compare them to the American-European Consensus Group (AECG) and ACR criteria in a Dutch prospective diagnostic cohort.Methods. Consecutive patients (n = 129) referred for suspicion of pSS underwent a multidisciplinary evaluation, including a labial and/or parotid gland biopsy. Patients with an incomplete work-up (n= 8) or associated systemic auto-immune disease (n= 7) were excluded. The ACR-EULAR classification was compared with expert classification, AECG and ACR classification. Additionally, the accuracy of individual ACR-EULAR items in discriminating pSS from non-pSS was evaluated. The validity of criteria sets was described separately using parotid or labial gland biopsy results for classification.Results. Of the 114 evaluated patients, the expert panel classified 34 (30%) as pSS and 80 (70%) as non-pSS. Using labial gland biopsy results, ACR-EULAR classification showed 87% absolute agreement (kappa = 0.73) with expert classification, with a sensitivity of 97% and specificity of 83%. Using the parotid gland biopsy results, the ACR-EULAR criteria performed excellently as well. Focus score, anti-SSA titre and ocular staining score showed good to excellent accuracy, whereas unstimulated whole saliva and Schirmer's test had poor accuracy. The ACR-EULAR and AECG criteria had equal validity. Compared with ACR classification, ACR-EULAR classification showed higher sensitivity but lower specificity.Conclusion. The ACR-EULAR criteria showed good agreement with expert classification, but some patients may be misclassified as pSS. Unstimulated whole saliva and Schirmer's test showed poor discriminative value. The ACR-EULAR criteria performed equally to the AECG criteria, and had higher sensitivity but lower specificity than the ACR criteria.

The rationale for B cell depletion therapy with rituximab in primary Sjogren's syndrome relies upon the well-established role of B cell hyperactivity in immunopathogenesis. In line with this notion, several biomarkers of B cell activity are significantly affected by treatment, both in the target organs and periphery. In contrast to most biological outcomes, clinical outcomes are not consistent between studies. Although two large RCTs did not meet their primary endpoint, several beneficial clinical effects of treatment have been shown. As discussed in this review, differences in study design and patient characteristics could explain the variation in results. Interestingly, a newly developed composite endpoint of subjective and objective outcomes did show a significant effect of rituximab in one of the large RCTs. Response predictors need to be identified to define more targeted inclusion criteria and achieve precision medicine. The positive effects seen on biological and clinical parameters warrant future studies to investigate this promising treatment modality.

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.

Dryness of epithelial surfaces is characteristic for patients with primary Sjogren’s syndrome (pSS). Vaginal dryness is frequently reported by pSS-women and is associated with sexual dysfunction.1 2 Recently, we showed that dysbiosis of the oral microbiome is largely similar between oral dryness patients with and without pSS when compared with healthy controls.3 4 The objective of our current study was to assess whether the vaginal microbiome of women with pSS-associated vaginal dryness differs from controls. In a case-control design, we compared the vaginal microbiome of 10 premenopausal pSS-women with that of 10 age-matched premenopausal women without pSS, who underwent general anaesthesia for a laparoscopic procedure. Exclusion criteria were genital inflammatory or infectious comorbidity, endometriosis and use of disease modifying antirheumatic drugs, corticosteroids, vaginal oestrogens or an intrauterine contraceptive device. All patients with pSS fulfilled the 2016 ACR/EULAR classification criteria. All participants completed a questionnaire on vaginal symptoms. Patient-reported vaginal dryness was scored using a Numeric Rating Scale (NRS, range 0–10). Vaginal health was assessed with the Vaginal Health Index (VHI).5 From all participants, a cervicovaginal lavage (CVL) and endocervical swab (ES) were collected. DNA from all samples was …

Background Patients with primary Sjogren’s syndrome (pSS) present with heterogeneous clinical symptoms and immune dysregulation. How immune dysregulation in SS arises is poorly understood, which hampers development of effective therapies. Identification of key immune pathways contributing to pSS pathogenesis is essential for successful drug development. Systemic treatment of patients early in the disease process will limit irreversible damage to salivary and lacrimal glands, as well as to other affected tissues. Objectives To identify early systemic biomarkers and dysregulated immune pathways in newly diagnosed pSS patients by multidimensional immuno-profiling. Methods We included 40 newly diagnosed pSS patients (39 female; mean age 51±14) and 20 age- and sex-matched non-SS sicca patients (19 female; mean age 50±13). All pSS patients fulfilled ACR-EULAR criteria. Serum and peripheral blood mononuclear cells (PBMC) were collected and cryopreserved. PBMCs were thawed for immunophenotyping by flow cytometry and RNA isolation. RNA sequencing was performed using TruSeq Stranded Total RNA Library Prep Gold (Illumina), following manufacturer’s recommendations, and RNAseq libraries were sequenced on a HiSeq2500 system. Additionally, serum proteomics and immunoassays for pro-inflammatory cytokines in serum were performed. Results Interferon (IFN) type I signaling pathways were at the top of enriched pathways in PBMCs from pSS patients, compared with non-SS sicca controls (adjusted p Conclusion Newly diagnosed patients with pSS show co-activation of the IFN type I and B cell activation pathways, compared to non-SS sicca controls. At the same time, CD4+ T cell subsets critical for B cell function are activated, which can enhance B cell activation and plasma cell formation. Personalized treatment based on the activity of each pathway in individual patients potentially increases the efficacy of such treatments. Acknowledgement Part of this work was funded by NIH grant RFA-DE-06-004 Disclosure of Interests Gwenny M. Verstappen: None declared, Lu Gao Employee of: Bristol-Myers Squibb, Sarah A. Pringle: None declared, Janneke H. Terpstra: None declared, Silvia C. Liefers: None declared, Jolien F. van Nimwegen Speakers bureau: Bristol-Myers Squibb, Arjan Vissink: None declared, Vishal Patel Employee of: Bristol-Myers Squibb, Aiqing He Employee of: Bristol-Myers Squibb, Amy Truong Employee of: Bristol-Myers Squibb, Sarah Hu Employee of: Bristol-Myers Squibb, Ashok Dongre Employee of: Bristol-Myers Squibb, Arathi Krishnakumar Employee of: Bristol-Myers Squibb, Stefan Kirov Employee of: Bristol-Myers Squibb, Julie Carman Employee of: Bristol-Myers Squibb, 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, 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

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.

Introduction: Primary Sjogren's syndrome (pSS) is a disabling auto-immune disease, affecting exocrine glands and several organs.Areas covered: In this review we analyze the safety of therapies used in pSS. Symptomatic treatment is widely applied due to the good supportive effect and good safety profile. Systemic stimulation of tears and saliva can be successful in pSS. However, cumbersome adverse events can influence the tolerability of this therapy. Evidence for the effectiveness of synthetic DMARDs therapies in pSS is limited, while there is a risk of adverse events. Several studies on biologic DMARD treatment of pSS patients have shown promising efficacy and safety results.Expert opinion: The safety of symptomatic treatment of pSS is very good. However, systemic therapy is necessary to achieve long-term relieve and prevention of organ-damage. Synthetic DMARDs have not shown much efficacy in earlier studies, and their benefits do not weigh up to the possible harms, while biologic DMARDs show promising results regarding efficacy and cause mostly mild adverse events. Many questions remain unanswered regarding safety of DMARDs in pSS. There is a need for well designed studies, in which safety should be evaluated in a uniform manner to be able to compare the results between studies.

Lymphoepithelial lesions (LELs) in salivary glands are associated with primary Sjögren's syndrome (pSS). LELs are composed of hyperplastic epithelium infiltrated with lymphocytes. The objective of this study was obtaining insight in the relative roles of intraepithelial B- and T-lymphocytes in the formation of LELs in salivary glands of pSS patients.Parotid and labial salivary gland biopsies of pSS patients (n=15), non-SS sicca patients (n=5) and non-sicca controls (n=5) were analysed. Serial sections were stained with HE and for cytokeratin, CD20 and CD3. Striated ducts with lymphocytes, but without hyperplasia, and striated ducts with LELs were identified in HE and cytokeratin stained sections. LELs were classified in successive stages of severity based on the amount of hyperplasia (stage1-3). Numbers of B- and T-lymphocytes within striated ducts and LELs were counted in CD20 and CD3 stained sections.Lymphocyte-containing striated ducts of both salivary glands of all pSS and control patients harboured T-lymphocytes, scattered throughout the ductal epithelium. In contrast, B-lymphocytes were exclusively found in a small fraction (21%) of striated ducts without hyperplasia and in nearly all striated ducts with LELs of pSS patients, but not in controls. In striated ducts with LELs B-lymphocytes were mostly located in the areas of proliferating epithelium. Numbers of B-lymphocytes and B/T-ratios increased significantly with higher severity of LELs. This was even more pronounced in the parotid than in the labial gland.We conclude there is an association between presence of intraepithelial B-lymphocytes and the formation of LELs in salivary glands of pSS patients.

To assess the inter- and intraobserver reliability of ultrasound of major salivary glands in patients clinically suspected of having primary Sjögren's syndrome (pSS) as well as to assess sources of variation in outcomes of ultrasonographic evaluation. 80 consecutive outpatients with clinically suspected pSS underwent ultrasound evaluation. The following ultrasound variables of the parotid and submandibular salivary glands were assessed: echogenicity, parenchymal homogeneity, presence of hypoechogenic areas, hyperechogenic reflections and clearness of posterior glandular border, according to the scoring system of Hocevar et al. (total score range: 0 - 48). Images were scored independently by three blinded observers in two sessions. The intraobserver reliability of the total ultrasound score was excellent, with an intraclass correlation (ICC) ranging from 0.89 to 0.96. The interobserver reliability was good to excellent, with ICCs of 0.84 and 0.76 for the total ultrasound score in the two sessions. The kappa value ranged from 0.60 to 0.83 depending on the applied cut-offs (cut-off score ≥ 15 and ≥ 17). Hypoechogenic areas and homogeneity of parotid glands showed the highest interobserver reliability. The median kappa for echogenicity was low. The total ultrasound scores varied more between observers in patients with higher ultrasonographic scores (approximately scores ≥ 20). Ultrasound of major salivary glands is a reliable imaging technique for patients with clinically suspected pSS. Discrepancies between observers in assessing the severity of ultrasound findings may interfere with detecting 'true' changes over time. When monitoring the progression of pSS or treatment efficacy, it is advised that a particular patient be scored by the same ultrasonographer at every time point.ZIEL: Beurteilung der Inter- und Intraobserver-Reliabilität des Ultraschalls der großen Speicheldrüsen bei Patienten mit klinischem Verdacht auf primäres Sjögren-Syndrom (pSS) und Bewertung der Schwankungsquellen der Sonografie-Ergebnisse. 80 aufeinander folgende ambulante Patienten mit klinischem Verdacht auf pSS wurden sonografisch bewertet. In der Glandula parotidea und Glandula submandibularis wurden die folgenden Ultraschallvariablen untersucht: Echogenität, Homogenität des Parenchyms, Nachweis von echoarmen Reflexionen und deutliche Abgrenzung des posterioren Drüsenrands nach dem Scoring-System von Hocevar et al. (gesamter Score-Bereich: 0 – 48). Die Bilder wurden unabhängig voneinander durch drei verblindete Beobachter in zwei Sitzungen eingeteilt. Die Intraobserver-Reliabilität der Gesamt-Ultraschall-Scores war ausgezeichnet, mit einer Intraklasse-Korrelation (ICC) zwischen 0,89 und 0,96. Die Interobserver-Reliabilität war gut bis ausgezeichnet, mit ICCs von 0,84 und 0,76 für den Gesamt-Ultraschall-Score in den beiden Sitzungen. Der kappa-Wert war zwischen 0,60 und 0,83 je nach verwendetem Cut-off (Cut-off Score ≥ 15 und ≥ 17). Echoarme Bereiche und die Homogenität der Parotisdrüsen zeigten die höchste Interobserver-Reliabilität. Der mediane Kappawert für die Echogenität war gering. Bei Patienten mit höheren Ultraschall-Scores variierten die Gesamt-Ultraschall-Scores stärker zwischen den Beobachtern (Scores von etwa ≥ 20). Die Sonografie der großen Speicheldrüsen ist eine zuverlässige bildgebende Diagnostik bei Patienten mit klinischem Verdacht auf pSS. Widersprüchliche Bewertungen des Schweregrads von Ultraschall-Befunden zwischen Beobachtern können den Nachweis "echter" Veränderungen im Laufe der Zeit stören. Bei der Überwachung der Progression des pSS oder der Wirksamkeit der Therapie wird empfohlen, dass ein bestimmter Patient jedes Mal vom selben Ultraschalldiagnostiker beurteilt wird.

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.

Objective. Prevalence of vaginal dryness and dyspareunia is high in women with primary SS (pSS). Our aim was to compare sexual function and sexual distress in women with pSS with healthy controls, as well as to assess parameters that are associated with sexual dysfunction and distress in pSS.Methods. Forty-six women fulfilling the American-European Consensus Group criteria for pSS [mean age 46.3 years (S.D. 10.5)] and 43 age-matched healthy controls were included. Participants completed self-administered questionnaires, namely the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), Multidimensional Fatigue Inventory (MFI), Hospital Anxiety and Depression Scale (HADS), Maudsley Marital Questionnaire (MMQ) and RAND 36-item Health Survey (RAND-36). In addition, the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) and Patient Reported Index (ESSPRI) were recorded in patients.Results. Women with pSS had impaired sexual function compared with healthy controls (median FSFI 20.6 vs 30.3, P Conclusion. Women with pSS have impaired sexual function and more sexual distress compared with healthy controls. Sexual function and distress are influenced by vaginal dryness and patient-reported symptoms of pSS as well as psychosocial factors.

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.

Sicca complaints (sensation of dry mouth and/or eyes) are present in about a quarter of the individuals above the age of 65 years old and are mainly due to medication. However, physiological changes that occur during aging might also lead to a diminished glandular function. These age-related changes are, at least in part, to be the consequence of decreased androgen levels. In addition to these physiological effects that occur during normal aging, sicca complaints can also be caused by Sjogren's syndrome (SS): a systemic auto-inflammatory disorder mainly affecting exocrine glands. Genetic factors, lowered levels of gonadal hormones and (viral) infections appear to contribute to the etiology of the syndrome. The incidence of SS is higher among aged individuals, which might be due to earlier diagnosis, as the onset of SS in an individual with age-related exocrine gland dysfunction lowers the threshold for sicca complaints. On the other hand, physiological aging might be considered as a risk factor for development of SS, resulting in a faster development of the syndrome. Differentiating physiological sicca complaints from SS in the elderly can be challenging, since apparently healthy individuals might present with auto-antibodies and lymphocytic infiltrates in salivary glands might be present as well. The drop in the level of androgens and estrogens upon aging, immunosenescence and pro-inflammatory features of the aging immune system may all contribute to the etiology of pSS in the elderly. In this review, we describe the physiological effects of aging and the influence of SS on exocrine gland morphology and function.

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. …