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).

Can ultrasound of the major salivary glands differentiate Sjögren's disease from its major mimics?

OBJECTIVES: Ultrasound of the major salivary glands (SGUS) is widely used to assess the major salivary glands in Sjögren's disease (SjD). Little is known, however, regarding the diagnostic accuracy of SGUS to differentiate SjD from its mimics. This study aims to investigate the diagnostic accuracy of SGUS in differentiating SjD from other diseases with salivary gland involvement. METHODS: SGUS was performed in 20 consecutive patients with SjD and 20 consecutive patients with well-established systemic disease, i.e., with either sarcoidosis, amyloidosis, HIV infection or chronic HCV infection. Images were scored independently by two blinded observers using the Hocevar scoring system. Diagnostic accuracy to discriminate between the patient (sub-)groups was explored. RESULTS: The accuracy of SGUS to differentiate SjD from other systemic diseases was excellent (area under ROC curve of 0.91). The optimal cut-off value to define positive or negative ultrasound for SS was 15. Sensitivity, specificity, positive predictive value and negative predictive value were high, varying from 85-90%, and diagnostic odds ratio was 51. SGUS was positive in the vast majority of SjD patients (n=18), but also in 2 patients with HIV infection and one patient with sarcoidosis. SGUS score differed significantly between patients with SjD and other systemic diseases (median 27 vs. 10, p<0.001) as well as between SjD patients and patients with either sarcoidosis, amyloidosis, HIV or HCV infection (all p<0.05). CONCLUSIONS: This study indicates that SGUS has a potentially high diagnostic accuracy to discriminate SjD from systemic diseases which can also cause salivary gland involvement.

Histopathology, salivary flow and ultrasonography of the parotid gland: three complementary measurements in primary Sjögren's syndrome.

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.

Patient Acceptable Symptom State (PASS) in patients with primary Sjögren's syndrome in daily clinical practice.

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).

Clinical determinants of vaginal dryness in patients with primary Sjögren's syndrome.

OBJECTIVES: 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. METHODS: 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 (p<0.05) were corrected for potential confounders. RESULTS: 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. CONCLUSIONS: 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.

Vaginal dryness in primary Sjögren's syndrome: a histopathological case-control study.

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.

Ten years of the ESSDAI: is it fit for purpose?

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.

Presence of intraepithelial B-lymphocytes is associated with the formation of lymphoepithelial lesions in salivary glands of primary Sjögren's syndrome patients.

OBJECTIVES: 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. METHODS: 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 H & E and for cytokeratin, CD20 and CD3. Striated ducts with lymphocytes, but without hyperplasia, and striated ducts with LELs were identified in H & E 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. RESULTS: 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. CONCLUSIONS: We conclude there is an association between presence of intraepithelial B-lymphocytes and the formation of LELs in salivary glands of pSS patients.

Scoring hypoechogenic areas in one parotid and one submandibular gland increases feasibility of ultrasound in primary Sjögren's syndrome.

OBJECTIVE: To 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). METHODS: Ultrasound 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. RESULTS: 116 (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). CONCLUSION: sUS 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.

Serum immunoglobulin free light chains are sensitive biomarkers for monitoring disease activity and treatment response in primary Sjögren's syndrome.

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 FLCκ/FLCλ was measured by nephelometry or turbidimetry. Results: At diagnosis, FLCκ and FLCλ serum levels were significantly higher in pSS compared with non-SS sicca patients. The FLCκ/FLCλ ratio was abnormal in 11% of pSS patients. In established MALT-pSS patients, without recent rituximab treatment (n = 12), 50% had abnormal FLCκ/FLCλ 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 FLCκ/FLCλ 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.

Validation of the ACR-EULAR criteria for primary Sjögren's syndrome in a Dutch prospective diagnostic cohort.

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 (κ = 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.

Ultrasound of the Major Salivary Glands is a Reliable Imaging Technique in Patients with Clinically Suspected Primary Sjögren's Syndrome.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The value of rituximab treatment in primary Sjögren's syndrome.

The rationale for B cell depletion therapy with rituximab in primary Sjögren'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.

Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjögren's syndrome.

OBJECTIVE: To 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). METHODS: 103 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). RESULTS: Absolute 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. CONCLUSION: In 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.

The impact of primary Sjögren's syndrome on female sexual function.

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 Sjögren'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 < 0.001), as reflected by significantly lower scores in the domains of desire, arousal, orgasm, lubrication and pain. Furthermore, pSS patients experienced more sexual distress (median FSDS 7 vs 4, P < 0.05) and were sexually active less frequently than controls (76% vs 93%, P < 0.05). Sexual dysfunction correlated significantly with patient-reported symptoms of pSS (ESSPRI), symptoms of fatigue (MFI), depressive symptoms (HADS), relationship dissatisfaction (MMQ) and lower mental quality of life (RAND-36), but not with systemic disease activity (ESSDAI). 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.

Increased Diagnostic Accuracy of the Labial Gland Biopsy in Primary Sjögren Syndrome When Multiple Histopathological Features Are Included.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of the labial salivary gland biopsy based on multiple histopathological features in patients with suspected primary Sjögren syndrome (pSS). METHODS: Patients from a diagnostic sicca cohort with clinically suspected pSS who underwent a labial gland biopsy were included. Patients were categorized as having pSS or non-Sjögren syndrome sicca (non-SS sicca) based on vignettes scored by an expert panel. Labial gland biopsies were analyzed for the presence of four histopathological features: focus score (FS) ≥1, prelymphoepithelial and lymphoepithelial lesions, immunoglobulin G plasma cell shift, and germinal centers. Sensitivity and specificity of histologic features were calculated, and the optimal cutoff value for the number of histopathological features needed to diagnose pSS was determined with receiver operating curve analysis. RESULTS: A total of 38 patients were categorized as having pSS and 65 as having non-SS sicca. In labial gland biopsies of patients with pSS, the prevalence of FS ≥1 was 82%, followed by 68% for pre-lymphoepithelial and lymphoepithelial lesions, 63% for plasma cell shift, and 24% for germinal centers. Although FS ≥1 showed the highest sensitivity for patients with pSS (82%), specificity was higher for the other three features (98%-100%). The presence of two or more (of four) histopathological features had almost comparable sensitivity to FS alone, but specificity increased with 12% to 100%. For fulfillment of American College of Rheumatology/EULAR criteria, specificity increased from 84% to 95% when an abnormal biopsy was defined by the presence of two or more histopathological features instead of FS ≥1 only. CONCLUSION: The diagnostic accuracy of the labial gland biopsy increases when other histopathological features besides FS are taken into account, by reducing the number of false-positive biopsies.

Long-term abatacept treatment for 48 weeks in patients with primary Sjögren's syndrome: The open-label extension phase of the ASAP-III trial.

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 ≤ 7 years and ESSDAI ≥ 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 Sjögren'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.