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.

Single immediate implant placement in the maxillary aesthetic zone with and without connective tissue grafting: Results of a 5-year randomized controlled trial.

AIM: To assess the 5-year effects of grafting connective tissue while undertaking single immediate implant placement and provisionalization at the mid-buccal mucosa level (MBML). Secondary outcomes were buccal bone wall thickness (BBT), marginal bone level (MBL) and patient satisfaction. MATERIALS AND METHODS: Sixty patients with a single failing tooth in the maxillary anterior region were provided with an immediately placed and provisionalized implant. At implant placement, the patients randomly received either a connective tissue graft from the maxillary tuberosity (n = 30, test group) or no graft (n = 30, control group). The alveolar socket classification was mainly Type 2A. Data were collected before removing the failing tooth (T0 ), and at 1 (T1 ), 12 (T12 ) and 60 (T60 ) months after final crown placement. The primary outcome was the change in MBML compared with the pre-operative situation. Additionally, the change in BBT, MBL, aesthetics (using the Pink Aesthetic Score-White Aesthetic Score), soft-tissue peri-implant parameters and patient satisfaction were assessed. RESULTS: At the 5-year follow-up, 27 patients could be analysed from each group. In each group, one implant was lost during the osseointegration period, within 3 months of placement, resulting in an implant survival rate of 96.7% in both groups. MBML change at T60 was -0.6 (-1.1 to -0.1) mm in the control group and 0.1 (-0.4 to 0.5) mm in the test group (p = .008). BBT and MBL, aesthetics, soft-tissue peri-implant parameters and patient satisfaction showed stable results and satisfied patients, without clinically relevant differences between the groups. CONCLUSIONS: This 5-year follow-up study shows that grafting connective tissue when replacing a single failing tooth with immediately placed and provisionalized implant results in favourable peri-implant tissues and fewer MBML changes.

Immediate implant placement with immediate or delayed provisionalization in the maxillary aesthetic zone: A 10-year randomized trial.

AIM: To compare the marginal bone level of immediately placed implants, with either immediate or delayed provisionalization (IP or DP), in the maxillary aesthetic zone after 10 years of function. MATERIALS AND METHODS: Participants with a failing tooth in the maxillary aesthetic zone were randomly assigned to immediate implant placement with either IP (n = 20) or DP (n = 20) after primary wound closure with a free gingival graft. The final restoration was placed 3 months after provisionalization. The primary outcome was change in marginal bone level. In addition, implant survival, restoration survival and success, peri-implant tissue health, mucosa levels, aesthetic indices, buccal bone thickness and patient satisfaction were evaluated. RESULTS: After 10 years, the mean mesial and distal changes in marginal bone level were -0.47 ± 0.45 mm and -0.49 ± 0.52 mm in the IP group and -0.58 ± 0.76 mm and -0.41 ± 0.72 mm in the DP group (p = .61; p = .71). The survival rate was 100% for the implants; for the restorations, it was 88.9% in the IP group and 87.5% in the DP group. Restoration success, according to modified USPHS criteria, was 77.8% in the IP group and 75.0% in the DP group. The prevalence of peri-implant mucositis was 38.9% and 35.7% and of peri-implantitis 0.0% and 6.3%, respectively, in the IP group and DP group (p = 1.0; p = .40). The Pink Esthetic Score and White Esthetic Score was 15.28 ± 2.32 in the IP group and 14.64 ± 2.74 in the DP group, both clinically acceptable (p = .48). The buccal bone thickness was lower in the DP group. Patient satisfaction was similar in both groups (p = .75). CONCLUSIONS: The mean marginal bone level changes after immediate implant placement with IP were similar to those after immediate placement with DP. CLINICAL TRIAL REGISTRATION: Registered in the National Trial Register (NL9340).

Single crowns in the posterior maxilla supported by either 11-mm long implants with sinus floor augmentation or by 6-mm long implants: A 10-year randomized controlled trial.

OBJECTIVES: To compare the clinical performance of single crowns in the posterior maxilla supported by either 11-mm long implants combined with maxillary sinus floor augmentation (MSFA) surgery or by 6-mm long implants during a 10-year follow-up period. MATERIALS AND METHODS: Subjects were randomly allocated to receive one 11-mm long implant in combination MFSA or to receive one 6-mm long implant without any grafting. Twenty-one implants in 20 patients were placed in the 6-mm group and 20 implants in 18 patients were placed in the 11-mm group. Both groups were followed by clinical and radiographic examinations up to 10 years. Patients' satisfaction was also scored before treatment. RESULTS: Two patients died and eight patients moved during the follow-up. Two patients lost an implant in the 6-mm group and one implant was lost in the 11-mm group (implant survival 89.5% and 90.9%, respectively). From loading to 10 years' follow-up, mean ± SE marginal bone loss in the 6-mm group and 11-mm group was 0.18 ± 0.10 mm and 0.26 ± 0.12 mm, respectively, without a significant difference between the groups at 10 years (p = .650). In both groups, indices scores for plaque, calculus, gingiva and bleeding were low as well as mean pocket probing depth. Patients' satisfaction at 10 years was high in both groups; mean overall satisfaction in the 6-mm group and 11-mm group was 9.6 ± 0.6 and 9.2 ± 0.8, respectively (p = .168). CONCLUSIONS: Placement of 6-mm implants or 11-mm implants combined MFSA are equally successful during a 10-year follow-up period when applied for supporting a single restoration.

Mechanical performance of patient-specific prefabricated temporary shell versus laboratory-fabricated CAD/CAM provisional implant-supported single-tooth restorations: A laboratory study.

OBJECTIVE: To evaluate the mechanical performance of patient-specific prefabricated temporary shell versus laboratory-fabricated CAD/CAM provisional restorations on titanium temporary abutments, with and without thermo-mechanical ageing. MATERIALS AND METHODS: Implants with a conical connection were divided into four groups (n = 24) and restored with temporary shell or laboratory-fabricated central or lateral incisor PMMA restorations that were relined or bonded on titanium temporary abutments. The diameter of the central and lateral incisor groups' implants was regular (ϕ 4.3 mm) or narrow (ϕ 3.5 mm), respectively. Half of each group's specimens were subjected to ageing, simultaneous thermocycling (5-55°C) and chewing simulation (120,000 cycles, 50 N, 1.7 Hz) resulting in eight groups in total (n = 12). The aged specimens were evaluated with optical microscopy, and survival and complication rates were determined according to modified USPHS criteria. The non-aged specimens and those that had survived ageing were loaded until failure, whereupon bending moments were calculated. RESULTS: Survival rates after ageing were 100% for all groups. Apart from wear facets (ϕ 2-3 mm) on the palatal restoration surface, no complications were observed. The mean fracture load and bending moments ranged between 597.6-847.1 N and 433.3-550.6 Ncm, respectively, with no significant differences between the eight groups (p = .25; p = .20). CONCLUSIONS: As patient-specific temporary shell central and lateral incisor provisional implant-supported restorations are mechanically stable enough to withstand clinical bite forces, even after thermo-mechanical ageing, they may serve as an alternative to laboratory-fabricated provisional restorations.

FDG-PET/CT discriminates between patients with and without lymphomas in primary Sjögren's syndrome.

OBJECTIVES: To assess the usefulness of [18F]-fluorodeoxyglucose (FDG)-PET/CT (i) to discriminate between primary SS (pSS) patients with and without lymphomas and (ii) to evaluate systemic disease activity in pSS. METHODS: ACR-EULAR-positive pSS patients who underwent FDG-PET/CT were included. Scans were visually evaluated and quantitative analysis was performed by measuring standardized uptake values (SUV) of salivary and lacrimal glands and systemic regions. Receiver operating characteristic curve analyses were performed to find SUV cut-off values to discriminate between lymphoma and non-lymphoma. RESULTS: Of the 70 included patients, 26 were diagnosed with a pSS-associated lymphoma, mostly of the mucosa-associated lymphoid tissue type (23/26). Lymphoma patients showed higher FDG uptake in the parotid and submandibular glands, and more frequently showed presence of nodular lung lesions, compared with non-lymphoma patients. The accuracy of the maximum SUV (SUVmax) in the parotid and submandibular gland to predict lymphoma diagnosis was good, with optimal cut-off points of 3.1 and 2.9. After combining these three visual and quantitative findings (nodular lung lesions, parotid SUVmax > 3.1 and submandibular SUVmax > 2.9), sensitivity was 92% when at least one of the three features were present, and specificity was 91% in case at least two features were present. Furthermore, FDG-PET/CT was able to detect systemic manifestations in pSS patients, mostly involving lymph nodes, entheses and lungs. CONCLUSIONS: FDG-PET/CT can assist in excluding pSS-associated lymphomas in patients without PET abnormalities, possibly leading to a decrease of invasive biopsies in suspected lymphoma patients. Furthermore, FDG-PET/CT is able to detect systemic manifestations in pSS and can guide to the best biopsy location.

The diagnostic power of salivary electrolytes for Sjögren's disease: a systematic literature review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to determine the power of salivary electrolytes for the diagnosis of Sjögren's disease (SjD). METHODS: A literature search was conducted (last search March 2023) using PubMed and Web of Science and completed with a manual search. Articles were screened for reports of human salivary ion concentrations, comparing SjD patients with healthy controls and/or sicca patients. Articles not using the SjD classification criteria or performing the classification as part of the experimental design were excluded. Forest plots were used to present the meta-analyses results for each ion, distinguishing between salivary type (unstimulated and stimulated whole saliva, submandibular/sublingual and parotid saliva). RESULTS: A total of 21 out of 722 articles were eligible for inclusion. For SjD patients a significant increase in salivary ion concentration was observed for sodium, chloride and calcium when comparing to healthy controls. Significant differences between SjD and sicca patients were noted for sodium, chloride, phosphate, calcium, phosphate, nitrite and nitrate. Stimulated whole saliva showed larger variability in results between studies in comparison to other types of saliva (unstimulated whole saliva, submandibular/sublingual saliva and parotid saliva). CONCLUSIONS: Despite differences in saliva type, salivary ion levels could be utilised for the screening for SjD. Making use of chloride in combination with sodium would be most promising for distinguishing SjD patients from healthy controls and adding phosphate to potentially make a distinguishment with sicca patients. Unstimulated whole saliva should be the first choice when testing salivary ion concentrations.

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.

Implant supported overdentures in Sjögren's disease patients: a multicentre prospective cohort study.

OBJECTIVES: To prospectively investigate patient-reported outcomes and clinical performance of implant supported overdentures in edentulous Sjögren's disease (SjD) patients compared to subjects without SjD. METHODS: 51 implants were placed in 12 patients with SjD and 50 implants in 12 non-SjD patients to support overdentures. Clinical performance, marginal bone-level changes, patient satisfaction and oral health related quality of life (OHRQoL) were assessed at 1 (T1), 6 (T6), 12 (T12) and 18 (T18) months after placement of the overdenture. Patient satisfaction, ability to chew and OHRQoL were assessed with validated questionnaires. Marginal bone-level changes were measured on standardised dental radiographs. Clinical parameters included implant and overdenture survival, plaque, bleeding and gingival indices, and probing depth. RESULTS: OHRQoL in patients with SjD improved significantly after placement of implant supported overdentures at all measuring moments compared to baseline (p<0.05). Nevertheless, ability to chew tough and hard food was significantly better for non-SjD patients at all timepoints after placement of an implant supported overdenture (p<0.05). Implant survival at T18 was 100% in the patients with SjD and 98% in the non-SS group. Mean marginal bone loss at T18 did not differ between patients with SjD and non-SS patients, 1.12±0.74 mm and 1.43±1.66 mm, respectively (p=0.58). Clinical performance was good with no differences between the groups for all outcome measures (p>0.05). CONCLUSIONS: Implant-supported overdentures have a positive effect on OHRQoL and dental implants can be successfully applied in edentulous patients with SjD with nearly similar outcomes as in non-SjD subjects.

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.

Maxillary overdentures supported by four or six implants in the anterior region: 10-year randomized controlled trial results.

AIM: To evaluate bar-supported maxillary implant overdenture treatment when supported by either four or six implants after 10 years. MATERIALS AND METHODS: Edentulous subjects with maxillary denture complaints and ample bone volume to facilitate implants in the anterior region of the maxilla were planned for implant overdenture treatment, randomized to receive either four implants (n = 25) or six implants (n = 25) and subsequently evaluated after 10 years of function. Outcome variables included peri-implant bone-level changes, implant and overdenture survival, complications, presence of plaque, calculus and bleeding, degree of peri-implant inflammation, probing depth and patient satisfaction. Differences between the groups and between evaluation periods were tested with a Student's t-test. RESULTS: Fourteen patients with totally 72 implants were lost to follow-up. Two patients from the six-implant group experienced implant loss (four implants), resulting in 96.1% implant survival in this group versus 100% survival in the four-implant group. Clinical, radiographical and patient-reported outcome measures did not differ statistically significant between the two groups. Patients from both groups were generally quite satisfied with the result after 10 years. CONCLUSIONS: Similar and favourable outcomes are seen in bar-supported maxillary overdentures on either four or six anteriorly placed implants after a 10-year evaluation period.

Site-specific radiation dosage and implant survival in oral cancer patients: A cohort study.

OBJECTIVES: We assessed the radiation dosages (Dmean ) on implant regions to identify the threshold for implant loss in patients with an intraoral malignancy treated with dental implants to support a mandibular denture during ablative surgery before volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: Data was collected prospectively from 28 patients treated surgically for an intraoral malignancy, followed by postoperative radiotherapy (VMAT) and analyzed retrospectively. Patients received 2 implants in the native mandible during ablative surgery. Implant-specific Dmean values were retrieved from the patients' files. Radiographic bone loss was measured 1 year after implant placement and during the last follow-up appointment. Implant survival was analyzed with the Kaplan-Meier method. Univariate logistic regression and Cox-regression analyses were performed to investigate the effect of increasing implant-specific radiation dosages on implant loss. RESULTS: Five out of 56 placed implants were lost during follow-up (median 36.0 months, IQR 39.0). Radiographically, peri-implant bone loss occurred in implants with a Dmean > 40 Gy. Implant loss occurred only in implants with a Dmean > 50 Gy. CONCLUSION: An implant-specific Dmean higher than 50 Gy is related to more peri-implant bone loss and, eventually, implant loss.

The minimally important difference for the Xerostomia Inventory among Sjögren's disease patients.

OBJECTIVE: Until now, the clinically relevant improvement for the Xerostomia Inventory (XI) has not been defined. Therefore, our aim was to determine the Minimally Important Difference (MID) of the XI for improvement in dry-mouth symptoms in SjD patients. METHOD: The study recruited 34 SjD patients who underwent sialendoscopy of major salivary glands and 15 SjD patients in a nonintervention control group. XI scores were assessed at several time points. The MID was determined from the mean difference in XI scores between the groups with and without improvement. RESULTS: In the control group, no significant XI score changes were seen. In the sialendoscopy group, a clinically relevant XI score change of four scale points was identified after 1 week. For a prolonged duration (≥16 weeks), a minimum reduction of seven scale points in the XI score was required to indicate clinically relevant improvement. CONCLUSION: In SjD patients, a minimum change of four points in the XI score indicates a clinically relevant improvement for evaluating short-term effects. For prolonged effects, a clinically relevant improvement requires a MID of seven points. The determination of the MID in XI could assist in future studies that evaluate changes in xerostomia.

Immune markers and microbial factors are related with periodontitis severity in people with HIV.

OBJECTIVE: The objective of the study is to assess systemic immune markers and microbial factors related to periodontitis severity in people living with HIV. METHODS: Eighty people living with HIV (PLWH), who exhibited in the last two viral load measurements < 40 copies/mL, underwent full-mouth periodontal examinations and sub-gingival plaque sampling. Periodontitis was classified according to the CDC-AAP case definition. Inflammation, immune-activation, and immunosenescence markers were assessed, microbiological analyses were performed, and oral care routines and HIV characteristics were noted. RESULTS: From our group of PLWH, 42.5% and 57.5% suffered from moderate and severe periodontitis, respectively. Oral care habits did not differ between PLWH with moderate and severe periodontitis. Bacterial subgingival plaque loads were higher, and Porphyromonas gingivalis was more prevalent in PLWH with severe periodontitis than with moderate periodontitis (53% vs 7%, respectively). Mean C-reactive protein levels [CRP, 1.6 mg/L versus 0.8 mg/L, p = 0.020] and percentages of senescent CD28-CD57 + CD8 + T-cells in peripheral blood [16.5 versus 8.9, p = 0.035] were higher with severe periodontitis. Infection duration, CD4 count, CD4/CD8 ratio and type of antiretroviral therapy did not differ between both groups. CONCLUSIONS: Periodontitis severity is related to increased prevalence of Porphyromonas gingivalis, elevated CRP levels, and higher frequencies of circulating CD8 + senescent cells in PLWH.

Impact of medications on salivary flow rate in patients with xerostomia: a retrospective study by the Xeromeds Consortium.

OBJECTIVES: This study evaluates the impact of systemic medications and polypharmacy on unstimulated (UWS) and chewing-stimulated whole saliva (SWS) flow rates in patients with xerostomia. MATERIAL AND METHODS: This cross-sectional multicenter study is based on data of patients referred to five oral medicine outpatient practices in Europe and USA from January 2000 and April 2014. Relevant demographic, social, medical history and current medications were collected. RESULTS: The study included 1144 patients, 972 (85%) females, with a mean (SD) age of 59 (14.1) years. In unmatched patients, the UWS flow rate was lower in patients taking a medication (vs. not taking a medication) from the following drug categories: opioid analgesics, anticonvulsants, antidepressants, antihypertensives, benzodiazepines, corticosteroids, diuretics, disease-modifying antirheumatic drugs (DMARDs) and hormones. There was a greater negative effect on SWS flow rate in patients taking (vs. not taking) anticonvulsants, antidepressants, benzodiazepines, corticosteroids, and DMARDs. In matched patients, both UWS (0.22 vs. 0.19 ml/min; p = 0.03) and SWS (0.97 vs. 0.85 ml/min; p = .017) flow rates were higher in patients on non-opioid analgesics (vs. not taking). The UWS flow rate was lower in patients taking antidepressants (vs. not taking) (0.16 vs. 0.22 ml/min p = .002) and higher (and within normal range) in patients taking sex hormones (vs. not taking) (0.25 vs. 0.16 ml/min; p = .005). On the other hand, SWS was lower in patients taking corticosteroid (vs. not taking) (0.76 vs. 1.07 ml/min; p = .002), and in patients taking DMARDs (vs. not taking) (0.71 vs. 0.98 ml/min; p = .021). Finally, differences in medians of both UWS and SWS were statistically significant in patients taking 1 or more than 1 opioid analgesic (vs. not taking, p ≤ .0001 and p = .031, respectively), 1 or more than 1 anticonvulsants (vs. not taking, p = .008 and p = .007), 1 or more than 1 antidepressants (vs. not taking, p < .0001 for both), 1 or more than 1 DMARDs (vs. not taking, p = .042, and p = .003). CONCLUSIONS: A greater negative impact on UWS and SWS flow rates was seen in patients taking more than one medication from the same drug class. Intake of antidepressants, corticosteroids and DMARDs is associated with lower whole saliva flow rates. CLINICAL RELEVANCE: Salivary flow rate can be modified by some specific medications, mostly by polypharmacy.

Digital image analysis of intraepithelial B-lymphocytes to assess lymphoepithelial lesions in salivary glands of Sjögren's syndrome patients.

OBJECTIVE: Salivary glands of primary SS (pSS) patients characteristically harbour periductal infiltrates, in which lymphoepithelial lesions (LELs) can develop. LELs are composed of hyperplastic ductal epithelium with infiltrating lymphocytes and may assist in the challenging diagnostic process of pSS. As manual identification of LELs remains difficult, we aimed to identify LELs by using an objective digital image analysis (DIA) algorithm that detects intraepithelial lymphocytes. METHODS: A virtual triple-staining technique developed for this study was used to count intraepithelial lymphocytes in consecutive slides stained for CD3 (T-lymphocytes), high-molecular-weight cytokeratin (hmwCK) (striated ducts) and CD20 (B-lymphocytes) in labial and parotid gland biopsies in a diagnostic cohort of 109 sicca patients. Patients were classified as having pSS or non-SS according to the ACR-EULAR classification criteria. RESULTS: T-lymphocytes were detected in almost all analysed ducts of pSS and non-SS sicca patients, whereas intraepithelial B-lymphocytes were present in 59-68% of labial and parotid gland biopsies of pSS patients, against only 2-3% of patients classified as non-SS. Intraepithelial B-lymphocytes were found in almost all striated ducts with hyperplasia (LELs). Remarkably, ∼25% of analysed striated ducts without hyperplasia of pSS patients also contained B-lymphocytes (precursor-LELs). Furthermore, presence of intraepithelial B-lymphocytes was associated with clinical parameters of pSS (i.e. serology). CONCLUSION: The presence of intraepithelial B-lymphocytes in salivary gland biopsies of sicca patients is a clear indicator of pSS and can be used as an objective alternative to LEL scoring. Therefore, identification of B-lymphocyte-containing ducts should be added to the diagnostic histopathological work-up of patients suspected of pSS.

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.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Selection of study endpoints and patients for clinical trials in primary Sjögren's syndrome.

In the last decade, many randomised controlled trials (RCTs) with biological DMARDs (bDMARDs) have been performed in patients with primary Sjögren's syndrome (pSS). Unfortunately, no bDMARD has yet been approved for systemic treatment of pSS. The heterogeneity of disease manifestations raises two essential questions: 1) which outcome measure is valid, reliable and responsive to demonstrate treatment efficacy and should be used as primary study endpoint? and 2) which pSS patients should be included in clinical trials? Both the selection of the primary study endpoint and the selection of patients are crucial and evolving issues in clinical trial design in pSS. This article summarises the history and comments the selection of primary study endpoints including the novel development of composite endpoints. Furthermore, this article gives an overview of inclusion criteria used for phase II and III trials, and illustrates by data-analysis based on two prospective observational cohorts that each additional selection criterion will (largely) decrease the number of eligible patients in daily clinical practice.

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).