More severe parotid gland histopathology in paediatric-onset than in adult-onset Sjögren's disease.

OBJECTIVES: The aim of this study was to assess the histopathological features of the parotid glands in patients with paediatric-onset Sjögren's disease (pedSjD) in comparison to patients with adult-onset Sjögren's disease (adSjD). METHODS: This study was performed in Groningen, the Netherlands. Patients with pedSjD from a diagnostic paediatric cohort (n=19), patients with adSjD from a diagnostic adult cohort (n=32) and patients with adSjD who participated in a clinical trial (n=42) with a baseline parotid gland biopsy were included. Parotid gland biopsies were analysed after (immuno)histological staining for SjD-related histopathological markers and compared between groups. RESULTS: All characteristic histopathological features of adSjD were also observed in pedSjD. There were no significant differences in lymphoepithelial lesions or immunoglobulin A (IgA)/IgG plasma cell shift between the pedSjD and the adSjD cohorts. However, compared with the diagnostic adSjD cohort (with comparable total EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores), pedSjD showed more severe lymphocytic infiltration as reflected by a higher focus score (p=0.003), a higher relative surface area of CD45+ infiltrate (p=0.041), higher numbers of B and T lymphocytes/mm2 (p=0.004 and p=0.029, respectively), a higher B/T lymphocyte ratio (p=0.013), higher numbers of CD21+ follicular dendritic cell networks/mm2 (p=0.029) and germinal centres (GC)/mm2 (p=0.002). Compared with the trial adSjD cohort, with significant higher total ESSDAI scores (p=0.001), only the B/T lymphocyte ratio and numbers of GC/mm2 were significantly higher in the pedSjD cohort (p=0.023 and p=0.018, respectively). CONCLUSION: Patients with pedSjD exhibit more pronounced histopathological features compared with patients with adSjD at diagnosis. Notably, the histopathology of patients with pedSjD aligns more closely with that observed in an adSjD clinical trial cohort, with even stronger B lymphocyte involvement.

Cell Composition Analysis of Matched Salivary Organoid and Adherent Cultures: Choose Your Sjögren Disease Research Tool Carefully.

Sjögren disease (SjD) is widely recognized by the presence of B cell-dominated lymphocytic infiltration in the salivary glands (SGs). Contrary to what was originally presumed, however, SG hypofunction in SjD is not strongly correlated with the degree of SG lymphocytic infiltration in the SGs.

Improvement of bone mineral density and new vertebral fractures during 8 years of TNF-α inhibition in patients with axial spondyloarthritis.

OBJECTIVE: In our prospective cohort with standardized bi-annual measurements of bone mineral density (BMD) and spinal radiographs, we evaluated the long-term course of BMD and the development of radiographic vertebral fractures (VFs) during 8 years of TNFi treatment in patients with radiographic axial spondyloarthritis (r-axSpA). METHODS: Consecutive axSpA patients from the GLAS cohort receiving TNFi for ≥8 years were included. Patients who received anti-osteoporotic treatment were excluded. Lumbar spine (LS) BMD was assessed at baseline, 1 year and bi-annually using DEXA. Radiographic VFs were evaluated using the Genant classification. RESULTS: 126 axSpA patients were included; 75 % male, mean age 42 ± 11 years, ASDAS 3.8 ± 0.8, median LS BMD Z-score -0.5 (IQR -1.4-0.7) and 20 % had radiographic VFs at baseline. Disease activity improved rapidly and sustained. LS BMD Z-score improved significantly up to 4 years compared to the previous time point and sustained thereafter. Median percentage of improvement compared to baseline was 8.9 % (2.8-15.8) and 7.2 % (2.2-14.7) after 4 and 8 years, respectively. Of 90 patients with baseline and 8-year radiographs, 14 (16 %) developed new VFs and 5 (6 %) showed an increase in severity of existing VFs. Of all 44 VFs present at 8 years, 30 % were grade 2 (n = 12) or grade 3 (n = 1). CONCLUSION: In r-axSpA patients treated with TNFi for 8 years, LS BMD Z-score increased significantly, especially during the first 4 year of treatment. Radiographic VFs continued to develop or progressed, irrespective of improvement in BMD. Therefore, clinical attention for trabecular bone loss is important in daily clinical practice.

Added value of the salivary gland ultrasonography OMERACT score in the ACR/EULAR classification criteria for Sjögren's disease.

OBJECTIVES: To assess whether addition of the salivary gland ultrasonography (SGUS) OMERACT score influences the performance of the 2016 ACR/EULAR classification criteria for Sjögren's disease (SjD) in daily clinical practice. METHODS: Patients visiting the Sjögren Expertise centre in the University Medical Center Groningen for a diagnostic trajectory because of a suspicion of SjD were included. SGUS was performed of both parotid and submandibular glands. ROC analysis was used to assess the accuracy to predict clinical diagnosis of SjD with the SGUS OMERACT score, and by adding the SGUS OMERACT score to the ACR/EULAR criteria. Furthermore, the performance of the SGUS OMERACT and total SGUS Hocevar score were compared. RESULTS: In total, 419 consecutive patients were included. ROC analysis of the highest SGUS OMERACT score out of all four salivary glands (range 0-3) showed good accuracy (AUC 0.849) to predict clinical diagnosis of SjD, comparable to the accuracy of the total SGUS OMERACT score (range 0-12; AUC 0.868) and total Hocevar score (range 0-48; AUC 0.864). When incorporating the highest SGUS OMERACT score (cut-off score of ≥2) as additional item in the ACR/EULAR criteria, accuracy remained excellent (AUC 0.974), and clinical diagnosis could be predicted with a sensitivity of 96.4% and specificity of 86.5%. CONCLUSION: The accuracy of the ACR/EULAR classification criteria for predicting the clinical diagnosis of SjD remained excellent after incorporating the SGUS OMERACT score and extends the diagnostic options in patients suspected with SjD.

Increased Interferon Signaling in Vaginal Tissue of Patients With Primary Sjögren Syndrome.

OBJECTIVE: Vaginal dryness is an important factor influencing sexual function in women with primary Sjögren syndrome (pSS). Previous studies showed a higher degree of inflammation in vaginal biopsies from patients with pSS compared to non-pSS controls. However, the molecular pathways that drive this inflammation remain unclear. Therefore, the aim of this study was to investigate inflammatory pathway activity in the vaginal tissue of patients with pSS. METHODS: Vaginal biopsies of 8 premenopausal patients with pSS experiencing vaginal dryness and 7 age-matched non-pSS controls were included. Expression of genes involved in inflammation and tissue homeostasis was measured using NanoString technology and validated using TaqMan Real-Time PCR. Vaginal tissue sections were stained by immunohistochemistry for myxovirus resistance protein 1 (MxA) and CD123 (plasmacytoid dendritic cells [pDCs]). RESULTS: The most enriched pathway in vaginal biopsies from patients with pSS compared to non-pSS controls was the interferon (IFN) signaling pathway (P < 0.01). Pathway scores for Janus kinase and signal transducer and activator of transcription (JAK-STAT) and Notch signaling were also higher (P < 0.01 for both pathways). Conversely, transforming growth factor-ß signaling and angiogenesis pathway scores were lower in pSS (P = 0.02 and P = 0.04, respectively). Differences in IFN signaling between patients with pSS and non-pSS controls were confirmed by PCR and MxA tissue staining. No CD123+ pDCs were detected in vaginal biopsies. IFN-stimulated gene expression levels correlated positively with CD45+ cell numbers in vaginal biopsies and serum anti-SSA/Ro positivity. CONCLUSION: Upregulation of IFN signaling in vaginal tissue of women with pSS, along with its association with tissue pathology, suggests that IFNs contribute to inflammation of the vaginal wall and potentially also to clinical symptomatology (ie, vaginal dryness).

Histopathological comparison of Sjögren-related features between paired labial and parotid salivary gland biopsies of sicca patients.

OBJECTIVES: To compare focus score (FS) and other histopathological features between paired labial and parotid salivary gland biopsies in a diagnostic cohort of suspected Sjögren's disease (SjD) patients. METHODS: Labial and parotid salivary gland biopsies were simultaneously obtained from patients with sicca complaints, suspected of having SjD. Biopsies were formalin fixed and paraffin embedded. Sections were stained with haematoxylin & eosin (H&E) and for CD3, CD20, CD45, cytokeratin, CD21, Bcl6, activation induced deaminase (AID), and IgA/IgG. FS and other histopathological features characteristic for SjD were analysed. RESULTS: Based on the expert opinion of three experienced rheumatologists, 36 patients were diagnosed as SjD and 63 as non-SjD sicca patients. When taking all patients together, absolute agreement of various histopathological features between labial and parotid biopsies was high and varied between 80% (FS) and 93% ((pre-)lymphoepithelial lesions (LELs)). More labial gland biopsies had a FS ≥ 1 compared with their parotid counterpart. Accordingly, the area of infiltrate was larger in labial gland biopsies. When considering only SjD patients, labial glands contained significantly less B-lymphocytes, GCs/mm2 and less severe LELs compared with parotid glands. CONCLUSION: Labial and parotid glands from SjD patients contain similar histopathological key features, and thus both glands can be used for diagnosis and classification of SjD. However, parotid salivary glands reveal more evident B-lymphocyte related features, while labial glands exhibit more inflammation, which may be partially unrelated to SjD.

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

Longitudinal evaluation of major salivary gland functioning in Sjögren's disease patients in a prospective standard-of-care cohort.

OBJECTIVES: To evaluate changes in major salivary gland functioning over time using salivary gland ultrasonography (SGUS), salivary flow measurements (sialometry), and patient-reported outcome measures (PROMs) in patients diagnosed with primary Sjögren's disease (SjD). METHODS: Consecutive outpatients from the ongoing prospective REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort, all fulfilling the ACR-EULAR classification criteria for SjD, were included. SGUS images assessed with the Hocevar and OMERACT scoring system, unstimulated and stimulated whole saliva (UWS/SWS), unstimulated and stimulated submandibular/sublingual saliva (uSMSLS/sSMSLS) and parotid saliva, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) general dryness, oral dryness, and Xerostomia Inventory were assessed at baseline (BL), 2-year (Y2) and 5-year (Y5) follow-up. RESULTS: In total, BL and Y2 data were available for 253 patients and 75 patients had already reached Y5. At group level, SGUS Hocevar (i.e., mean±SD: 22±10 at BL, 22±10 at Y2 and 23±10 at Y5), OMERACT scores, UWS, SWS and PROMs remained stable over time (all p>0.05). Slightly decreased uSMSLS (p=0.025) and sSMSLS (p=0.004) were observed at Y5. At individual patient level, a similar proportion showed an increase or decrease of ≥25% for Hocevar, UWS and SWS. At baseline, poor associations were observed between SGUS and PROMs and fair associations between sialometry and PROMs. Over time, changes in objective assessments did not correlate with changes in PROMs. CONCLUSIONS: Overall, major salivary gland functioning assessed with SGUS, sialometry and PROMs did not change significantly up to 5 years of follow-up in a standard-of-care cohort of SjD patients from daily clinical practice.

Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS): development and validation of a novel outcome measure.

BACKGROUND: Recent randomised controlled trials (RCTs) in primary Sjögren's syndrome used the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjögren'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 Sjögren's syndrome: the Composite of Relevant Endpoints for Sjögren'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 Sjögren'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<0·0001) in ASAP-III, 49% (33 of 67) for rituximab versus 30% (20 of 66) for placebo (p=0·026) in the TRACTISS trial, 45% (41 of 92) for abatacept versus 32% (30 of 95) for placebo (p=0·067) in the multinational abatacept trial, and 18% (10 of 55) for tocilizumab versus 24% (13 of 55) for placebo (p=0·48) in the ETAP trial. INTERPRETATION: The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjögren'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.

Abatacept treatment for patients with early active primary Sjögren's syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study).

BACKGROUND: Several small open-label studies have suggested efficacy of abatacept-a co-stimulation inhibitor-in patients with primary Sjögren's syndrome. These promising results warranted further evaluation. We therefore aimed to further assess the safety and efficacy of abatacept compared with placebo in patients with primary Sjögren's syndrome. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial at the University Medical Center Groningen (Groningen, Netherlands). We included patients with primary Sjögren's syndrome fulfilling the American-European Consensus Group criteria, aged 18 years or older, with positive salivary gland biopsies, time from diagnosis of 7 years or less, and a European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or more. Independent pharmacists randomly allocated patients (1:1) to either the abatacept group or placebo group using a computer-generated sequence stratified by previous use of disease-modifying anti-rheumatic drugs. Patients received at-home subcutaneous injections of abatacept (125 mg) or placebo once a week for 24 weeks. The primary outcome was the between-group difference in ESSDAI score at week 24. Efficacy was analysed in patients who received at least one drug dose and for whom post-baseline data were collected. Safety was analysed in all patients who received at least one drug dose. FINDINGS: Between Aug 14, 2014, and Aug 23, 2018, 580 patients were reviewed for eligibility, of which 80 patients were randomly assigned to receive study treatment. Efficacy was analysed in 40 patients receiving abatacept and 39 patients receiving placebo (one patient in this group was lost to follow-up). The primary outcome did not significantly differ between the treatment groups. The adjusted mean difference in ESSDAI score at week 24 between the abatacept group and placebo group was -1·3 (95% CI -4·1 to 1·6). No deaths or treatment-related serious adverse events occurred. In 38 (95%) of 40 patients in the abatacept group, 103 adverse events occurred, including one serious adverse event and 46 infections. In 38 (95%) of 40 patients in the placebo group, 87 adverse events occurred, including four serious adverse events and 49 infections. INTERPRETATION: On the basis of this trial, we cannot recommend abatacept treatment as standard of care to reduce systemic disease activity in patients with primary Sjögren's syndrome. Further studies should evaluate whether patients with specific clinical manifestations and biological characteristics might benefit from abatacept treatment. FUNDING: Bristol-Myers Squibb.