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Objective: Systemic features influence disease prognosis and choice of treatment in primary Sjogren's syndrome (pSS). Our aim was to investigate the prevalence of pulmonary involvement in pSS patients and to classify patients according to the pulmonary domain of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI). Methods: This retrospective cohort study included consecutive pSS patients, fulfilling American-European Consensus Group/American College of Rheumatology classification criteria, who visited the Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, in 2015. Data on pulmonary complaints and pulmonary tests were obtained from electronic patient records. Pulmonary involvement was recorded if therapy was needed or follow-up was recommended, and when it was possibly or assumed to be related to pSS instead of coincidental factors. Results: Of the 262 included pSS patients, 88 (34%) had pulmonary complaints, mostly cough or dyspnoea on exertion. Pulmonary diagnostics were performed in 225 patients (86%). Pulmonary involvement was present and assumed to be related to pSS in 25 patients (10%) and possibly related to pSS in 14 (5%). Interstitial lung disease (ILD, n = 15), especially non-specific interstitial pneumonia (n = 7), was present most commonly. In total, 16 patients (6%) were scored as low (n = 4), moderate (n = 11), or high activity (n = 1) on the ESSDAI pulmonary domain. Conclusion: In this cross-sectional study in daily clinical practice, pulmonary involvement was present in 10-15% of pSS patients, of which ILD was most common. Of all pSS patients, 6% were scored as active on the pulmonary domain of the ESSDAI.

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.

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.

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 …

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.

The clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity–dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFasL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non–Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells. [Cancer Res 2008;68(2):597–604]

ObjectiveTo perform a systematic review and meta-analysis on studies examining the properties of ultrasonography of major salivary glands for diagnosing Sjogren's syndrome.Materials and MethodsWe searched for the literature on eight databases. The quality of included articles was assessed with the QUADAS-2 tool. Publication bias, pooled sensitivity, specificity, diagnostic odds ratio, and 95% confidence intervals (95%CI) were calculated. Meta-regression analysis was performed.ResultsWe identified 37 studies and 33 ultrasonographic scoring systems. High risk of bias was observed in patient selection', conduct and interpretation of ultrasound', and flow of patients and timing of tests' in 78%, 70%, and 51% of the studies. We included 29 studies in the meta-analysis. Publication bias was highly probable. Pooled sensitivity was 0.69 (95%CI: 0.67-0.71), specificity 0.92 (95%CI: 0.91-0.93), and diagnostic odds ratio 33.89 (95%CI: 20.75-55.35). Significant heterogeneity was detected between studies. Meta-regression analysis showed that studies with high risk of bias in conduct and interpretation of ultrasound' and studies evaluating only parenchymal homogeneity had higher log diagnostic odds ratio (1.09 and 2.49, respectively, pConclusionsThe quality of current studies is low, thus not allowing to judge the likelihood of salivary gland ultrasonography as a reliable and practical tool in diagnosing Sjogren's syndrome.

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

This paper describes a bi-specific antibody, which was called BIS20x3. It retargets CD3ɛ-positive cells (T-cells) to CD20-positive cells and was obtained by hybrid–hybridoma fusion. BIS20x3 could be isolated readily from quadroma culture supernatant and retained all the signalling characteristics associated with both of its chains. Cross-linking of BIS20x3 on Ramos cells leads to DNA fragmentation percentages similar to those obtained after Rituximab-cross-linking. Cross-linking of BIS20x3 on T-cells using cross-linking F(ab′)2-fragments induced T-cell activation. Indirect cross-linking of T-cell-bound BIS20x3 via Ramos cells hyper-activated the T-cells. Furthermore, it was demonstrated that BIS20x3 effectively re-targets T-cells to B-cells, leading to high B-cell cytotoxicity. The results presented in this paper show that BIS20x3 is fully functional in retargeting T-cells to B-cells and suggest that B-cell lymphomas may represent ideal targets for T-cell retargeting bi-specific antibodies, because the retargeted T-cell is maximally stimulated in the presence of B-cells. Additionally, since B-cells may up-regulate CD95/ Fas expression upon binding of CD20-directed antibodies, B-cells will become even more sensitive for T-cell mediated killing via CD95L/ Fas L, and therefore supports the intention to use T-cell retargeting bi-specific antibodies recognizing CD20 on B-cell malignancies as a treatment modality for these diseases. © 2001 Cancer Research Campaign http://www.bjcancer.com