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ObjectivesTo 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.MethodsACR-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.ResultsOf 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.ConclusionsFDG-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.

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.

Primary Sjögren's syndrome (pSS) is a rare disease in paediatric patients. Presenting symptoms differ from those in adult patients. The aim of this study was to evaluate presenting symptoms, classification criteria and clinical assessments, including salivary gland ultrasonography (SGUS), at disease onset in paediatric and adult patients with pSS.Data of 23 paediatric- and 33 adult-onset patients with pSS were obtained from our standardised multidisciplinary REpSULT and RESULT cohorts, respectively. Clinical, patient-reported, serological, functional, biopsy and SGUS parameters were compared.In paediatric-onset pSS (pedSS) patients, recurrent parotid gland swelling (91% vs. 49%, p0.001) and fever (30% vs. 3%, p=0.006) were more often present than in adult-onset patients. In contrast, sicca symptoms of mouth (52% vs. 79%, p=0.046) and eyes (26% vs. 73%, p0.001) were less common in pedSS patients. In paediatric patients, the entry criteria of the ACR/EULAR classification were most often met due to activity in the glandular domain of the ESSDAI. When applying the ACR/EULAR classification criteria, only 78% of pedSS fulfilled these criteria compared to 100% of adult patients. Abnormal glandular function tests had a greater contribution to fulfilling the criteria in adults, while the biopsy had a greater contribution in paediatric patients. Anti-SSA/Ro serology had similar contribution for both cohorts. SGUS Hocevar score was significantly higher in paediatric compared to adult patients (median 25 vs. 18, p=0.004).PedSS has a different presentation than adult-onset pSS. Recurrent parotid gland swelling in paediatric patients should alert clinicians to the potential presence of pSS.

Manasson et al 1 wrote an interesting review on what is known with regard to the application of microbiome research for diagnostic and research purposes within autoimmunity and rheumatology. The authors focused this review on the connection between the microbiome and rheumatoid arthritis (RA) as for long it has been presumed that microbiota are contributors to the development and progression of RA. Besides RA, the review also discussed microbiome studies in systemic lupus erythematosus (SLE) and systemic sclerosis. Remarkably, no attention was paid by Manasson et al to the potential involvement of the microbiome in Sjogren’s syndrome (SS). SS is the second most prevalent systemic rheumatic autoimmune disease after RA and the potential involvement of the microbiome in SS-patients is yet also extensively reported. The current knowledge on the relationship between the human microbiome and SS reveals possible pathogenic mechanisms and forms a basis for future treatment options through influencing the microbiome. Thus, the current knowledge on the SS–microbiome connection is an important addition to the review of Manasson et al .1 Thus far, all studies that compared the gut microbiome of SS patients with healthy or population controls have shown that the composition of the gut microbiome in SS patients differs from controls.2–7 Mandl et al 3 found that severe intestinal …

Total joint replacement (TJR) with a prosthesis can be indicated for patients with severe temporomandibular joint (TMJ) dysfunction. Surgical accuracy is necessary for correct translation of the preoperatively predicted functional outcome, wear, and biomechanical behaviour of the patient-specific TMJ-TJR prosthesis. This study describes the first clinical applications of the patient-specific TMJ-TJR prosthesis according to the Groningen principles (G-TMJ-TJR), which was developed and validated in a prior human cadaver test study. The aim of this study was to validate the accuracy of placement of the patient-specific G-TMJ-TJR in the clinical setting. It was hypothesized that a virtual surgical plan (VSP) combined with guided placement of the patient-specific G-TMJ-TJR would be performed as predictably and accurately as in the prior cadaver series. All patients who received a VSP-based patient-specific G-TMJ-TJR between December 2017 and March 2020 were included in this study. The accuracy analysis was based on postoperative cone beam computed tomography (CBCT) data. All 11 prostheses could be inserted using routine pre-auricular and retromandibular surgical approaches. Analysis of the VSPs and postoperative CBCTs showed an average three-dimensional deviation of 1.07 mm (standard deviation 0.46 mm, range 0.33?1.91 mm) for all of the fossa and mandibular components. The patient-specific G-TMJ-TJR can be applied predictably and accurately in a clinical setting.

The aim of this study was to investigate the value of 3D Statistical Shape Modelling for orthognathic surgery planning. The goal was to objectify shape variations in the orthognathic population and differences between male and female patients by means of a statistical shape modelling method. Pre-operative CBCT scans of patients for whom 3D Virtual Surgical Plans (3D VSP) were developed at the University Medical Center Groningen between 2019 and 2020 were included. Automatic segmentation algorithms were used to create 3D models of the mandibles, and the statistical shape model was built through principal component analysis. Unpaired t-tests were performed to compare the principal components of the male and female models. A total of 194 patients (130 females and 64 males) were included. The mandibular shape could be visually described by the first five principal components: (1) The height of the mandibular ramus and condyles, (2) the variation in the gonial angle of the mandible, (3) the width of the ramus and the anterior/posterior projection of the chin, (4) the lateral projection of the mandible’s angle, and (5) the lateral slope of the ramus and the inter-condylar distance. The statistical test showed significant differences between male and female mandibular shapes in 10 principal components. This study demonstrates the feasibility of using statistical shape modelling to inform physicians about mandible shape variations and relevant differences between male and female mandibles. The information obtained from this study could be used to quantify masculine and feminine mandibular shape aspects and to improve surgical planning for mandibular shape manipulations.

Objectives In case of surgical removal of oral squamous cell carcinomas, a resection of mandibular bone is frequently part of the treatment. Nowadays, such resections frequently include the application of 3D virtual surgical planning (VSP) and guided surgery techniques. In this paper, current methods for 3D VSP leads for optimisation of the workflow, and patient-specific application of guides and implants are reviewed. Recent findings Current methods for 3D VSP enable multi-modality fusion of images. This fusion of images is not restricted to a specific software package or workflow. New strategies for 3D VSP in Oral and Maxillofacial Surgery include finite element analysis, deep learning and advanced augmented reality techniques. These strategies aim to improve the treatment in terms of accuracy, predictability and safety. Conclusions Application of the discussed novel technologies and strategies will improve the accuracy and safety of mandibular resection and reconstruction planning. Accurate, easy-to-use, safe and efficient three-dimensional VSP can be applied for every patient with malignancies needing resection of the mandible.

Pretreatment dental screening aims to locate and eliminate oral foci of infection in order to eliminate local, loco‐regional, or systemic complications during and after oncologic treatment. An oral focus of infection is a pathologic process in the oral cavity that does not cause major infectious problems in healthy individuals, but may lead to severe local or systemic inflammation in patients subjected to oncologic treatment. As head and neck radiotherapy patients bear a lifelong risk on oral sequelae resulting from this therapy, the effects of chemotherapy on healthy oral tissues are essentially temporary and reversible. This has a large impact on what to consider as an oral focus of infection when patients are subjected to, for example, head and neck radiotherapy for cancer or intensive chemotherapy for hematological disorders. While in patients subjected to head and neck radiotherapy oral foci of infection have to be removed before therapy that may cause problems ultimately, in patients that will receive chemotherapy such, so‐called chronic, foci of infection are not in need of removal of teeth but can be treated during a remission phase. Acute foci of infection always have to be removed before or early after the onset of any oncologic treatment.

Background Deficits in global oral health care are paramount, and complications of odontogenic infections constitute a considerable global health problem, particularly in low-income countries. A high mortality rate has been observed for patients who have been admitted with complicated odontogenic infections to our facilities in Tonkolili District, Sierra Leone, although exact data have not been published yet. Data regarding who in this region is at risk and why are lacking. Objective The Dental Abscess Study (DELAY) aims to prospectively investigate morbidity and mortality from complicated dental abscesses and to analyze patients’ characteristics and microbial findings to examine predisposing factors for poor outcomes. In particular, the incidence and the clinical and microbial characteristics of complicated odontogenic infections, as well as the sociodemographic data and comorbidities of affected patients, will be studied to develop improved management algorithms based on circumstance-specific factors. Methods Patients who present with complicated dental infections requiring hospital admission in Masanga Hospital or Lion Heart Medical Centre will be consecutively selected for possible inclusion in the study (starting on September 4, 2021) over a study period of 1 year, and individual routine follow-ups will be conducted at least 3 months after discharge. The results of standardized questionnaires will be obtained, and clinical measurements as well as medical photos will be taken. Standard laboratory tests (eg, full blood count and HIV status tests) will be performed, and pus specimens will be examined. Local treatment guidelines will be adhered to, and data on medical and surgical treatment as well as data on outcomes will be collected. The study results will be reported according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria. Routine follow-ups will take place at 1 and 3 months postdischarge. Results The DELAY protocol was endorsed by the Masanga Medical Research Unit’s Scientific Review Committee on June 16, 2021, and ethical approval was granted on July 5, 2021, by the Sierra Leone National Ethics Committee. The funding of the budgeted study costs was approved by Dental Health International Netherlands in August 2021. The projected start date of data collection was September 4, 2021, and the study period will most likely last for 1 year. As such, data collection is expected to be complete in November 2022. Conclusions The aim of our prospective observational cohort study is to gain more knowledge about complicated odontogenic infections in Tonkolili District, Sierra Leone, to further improve treatment strategies. International Registered Report Identifier (IRRID) DERR1-10.2196/33677

Prevalence data on severe dental infections is scarce, particularly for low-income countries. Patients with dental abscess complications who presented from September 2020 until December 2020 in two hospitals in Tonkolili District, Sierra Leone, were included into this case series. We report on a total of 20 patients, median age 28 years, with severe complications of dental abscesses, with a mortality rate of 45%. This case series illustrates the severity of the dire consequences of the absence of access to basic dental and oral healthcare.

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.

OBJECTIVE: Alterations in the microbiota composition of the gastro-intestinal tract are suspected to be involved in the etiopathogenesis of two closely related systemic inflammatory autoimmune diseases: primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Our objective was to assess whether alterations in gut and oral microbiota compositions are specific for pSS and SLE.METHODS: 16S ribosomal RNA gene sequencing was performed on fecal samples from 39 pSS patients, 30 SLE patients and 965 individuals from the general population, as well as on buccal swab and oral washing samples from the same pSS and SLE patients. Alpha-diversity, beta-diversity and relative abundance of individual bacteria were used as outcome measures. Multivariate analyses were performed to test associations between individual bacteria and disease phenotype, taking age, sex, body-mass index, proton-pump inhibitor use and sequencing-depth into account as possible confounding factors.RESULTS: Fecal microbiota composition from pSS and SLE patients differed significantly from population controls, but not between pSS and SLE. pSS and SLE patients were characterized by lower bacterial richness, lower Firmicutes/Bacteroidetes ratio and higher relative abundance of Bacteroides species in fecal samples compared with population controls. Oral microbiota composition differed significantly between pSS patients and SLE patients, which could partially be explained by oral dryness in pSS patients.CONCLUSIONS: pSS and SLE patients share similar alterations in gut microbiota composition, distinguishing patients from individuals in the general population, while oral microbiota composition shows disease-specific differences between pSS and SLE patients.

ObjectiveSalivary gland (SG) progenitor cells (SGPCs) maintain SG homeostasis. We have previously shown that in primary Sjögren’s syndrome (pSS), SGPCs are likely to be senescent, and may underpin SG dysfunction. This study assessed the extent of senescence of cells in a SGPC niche in pSS patients’ SGs, and its correlation with functional and clinical parameters.MethodsThe expression of p16 and p21 as markers of senescence in both total SG epithelium and a SGPC niche (basal striated duct cells, BSD) was examined in SGs of pSS (n = 35), incomplete pSS (n = 13) (patients with some signs of pSS, but not fulfilling all classification criteria) and non-SS sicca control (n = 21) patients. This was correlated with functional and clinical parameters.ResultspSS patient SGs contained significantly more p16+ cells both in the epithelium in general (P ConclusionThese findings suggest SGPC senescence may be an early feature of primary Sjögren’s syndrome and may contribute to defective SG function in pSS but not to systemic disease activity.

Background: Salivary glands (SGs) can be damaged by immune checkpoint inhibitor (ICI) therapy. In patients with ICI-induced SG dysfunction, 60% progress to fulfill classification criteria for primary Sjogren's syndrome (pSS), owing to immune foci in SGs and/or anti-SSA autoantibody positivity. We report the SG tissue analysis of a patient with SG dysfunction after treatment with a programmed death ligand-1 (PD-L1) inhibitor, compared to that of a dry mouth ("sicca") control and pSS patient.Case presentation: The patient received the PD-L1 inhibitor durvalumab (10 mg/kg, every 2 weeks by intravenous infusion) as adjuvant treatment for stage 3 non-small cell lung carcinoma, following concurrent chemo radiotherapy. At 43 weeks after 21 cycles of Durvalumab, the patient was not capable of producing unstimulated or stimulated parotid gland saliva, and a biopsy was taken. Immunohistochemical analysis showed no classical AQP5(+) CK7(-) acinar cell clusters (CK7 marks intercalated ducts, IDs). In contrast, the parenchyma was dominated by hybrid epithelial "structures" with ID-like morphology, containing a mixture of AQP5(+)CK7(-), AQP5(-)CK7(+), and AQP5(+)CK7(+) cells (30 structures/mm(2)). These structures were present at lower frequencies in sicca control (2/mm(2)) and pSS (10/mm(2)) tissue. Hybrid structures contained proliferating (Ki67(+)) cells and senescent (p16(+)) cells. Striated ducts showed no abnormal morphology post PD-L1 treatment, in contrast to pSS tissue. PD-L1 expression was detected in the SG parenchyma following anti-PD-L1 therapy. The SG post-PD-L1 therapy further demonstrated focal lymphocytic sialadentitis, harboring disperse, and focal CD4(+) T cell-rich infiltrates. CD8(+) T cells were also present. In this patient, these CD4(+) and CD8(+) T cells were observed in-between and inside hybrid structures. CD20(+) B-cells were infrequently detected following PD-L1 blockade, in contrast to their preponderance in pSS SG tissue.Conclusion: This patient lacked conventional SG acinar cells following anti-PD-L1 therapy and demonstrated presence of hybrid intercalated duct-like structures. Understanding which mechanisms and dynamics underpinning this aberrant parenchyma may be crucial to understand how SG dysfunction post ICI therapy, and potentially other affected organs. Furthermore, although the patient treated with anti-PD-L1 antibody examined here fulfills the criteria for pSS and demonstrated focal lymphocytic sialadentitis, the further histopathological characteristics do not resemble pSS.

Contains fulltext : 229342.pdf (Publisher’s version ) (Closed access) Three-dimensional stereophotogrammetry is commonly used to assess volumetric changes after facial procedures. A lack of clear landmarks in aesthetic regions complicates the reproduction of selected areas in sequential images. A three-dimensional volumetric analysis was developed based on a personalized aesthetic template. The accuracy and reproducibility of this method were assessed. Six female volunteers were photographed using the 3dMDtrio system according to a clinical protocol, twice at baseline (T1) and twice after 1year (T2). A styrofoam head was used as control. A standardized aesthetic template was morphed over the baseline images of the volunteers using a coherent point drift algorithm. The resulting personalized template was projected over all sequential images to assess surface area differences, volume differences, and root mean square errors. In 12 well-defined aesthetic areas, mean average surface area and volume differences between the two T1 images ranged from -7.6mm(2) to 10.1mm(2) and -0.11cm(3) to 0.13cm(3), respectively. T1 root mean square errors ranged between 0.24mm and 0.62mm (standard deviation 0.18-0.73mm). Comparable differences were found between the T2 images. An increase in volume between T1 and T2 was only observed for volunteers who gained in body weight. Personalized aesthetic templates are an accurate and reproducible method to assess changes in aesthetic areas.

Objectives: 3D virtual surgical planning (VSP) and guided surgery has been proven to be an effective tool for resection and reconstruction of the mandible. Currently, most widely used 3D VSP approaches to mandibular resection do not include detailed tumour information in the VSP. This manuscript presents a strategy where the aim was to incorporate tumour visualisation into the 3D virtual plan. Three-dimensional VSP of the mandibular resections was based on the fusion of CT and MRI data which was subsequently applied in clinical practice.Methods: All patients diagnosed with oral squamous cell carcinoma between 2014 and 2017 at the University Medical Centre Groningen were included. The tumour was delineated on the MRI data, after which this dataset was fused with the CT bone data in order to construct a 3D bone and tumour model for virtual resection planning. Guided resections were performed and post-operative evaluation quantified the accuracy of the resection. The histopathological findings and patient and tumour characteristics were compared to those of a historical cohort (2009-2014) of conventional mandibular continuity resections.Results: Twenty-four patients were included in the cohort. The average deviation from planned resection was found to be 2.2 mm. Histopathologic analysis confirmed all resection planes (bone) were tumour free, compared to 96.4% in the historic cohort.Conclusion: MRI-CT base tumour visualisation and 3D resection planning is a safe and accurate method for oncologic resection of the mandible. It is an improvement on the current methods reported for 3D resection planning based solely on CT data.

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.

OBJECTIVES: Patients suffering from osteoarthritis, ankylosis (e.g. post-trauma or tumour) in the temporomandibular joint (TMJ) can present with symptoms such as severely restricted mouth opening, pain or other dynamic restrictions of the mandible. To alleviate the symptoms, a total joint prosthesis can be indicated, such as the Groningen TMJ prosthesis. This was developed as a stock device with a lowered centre of rotation for improved translational and opening capacity. This study aimed to improve the design of the prosthesis, and produce a workflow for a customized Groningen TMJ prosthesis, in order to make it more accurate and predictable.METHODS: The fossa and mandibular components of the Groningen TMJ prosthesis were customized. A series of five human cadavers was operated and bilateral TMJ prostheses were placed using custom cutting and drilling guides. Placement accuracy was evaluated based on post-operative CT data.RESULTS: A total of N = 10 prostheses were placed and analysed. The average Euclidean distance deviation from planned to actual position was 0.81 mm (SD 0.21). All prostheses were placed according to the routine surgical approaches and had an excellent alignment with the bony structures.CONCLUSION: The newly developed custom Groningen TMJ prosthesis can be placed with great accuracy and is the first step for improving TMJ total joint replacement surgery.

In healthy subjects, dental implants have evolved to be a common therapy to solve problems related to stability and retention of dentures as well as to replace failing teeth. Although dental implants are applied in medically compromised patients, it is often not well known whether this therapy is also feasible in these patients, whether the risk of implant failure and developing peri-implantitis is increased, and what specific preventive measures, if any, have to be taken when applying dental implants in these patients. Generally speaking, as was the conclusion by the leading review of Diz, Scully, and Sanz on placement of dental implants in medically compromised patients (JDent, 41, 2013, 195), in a few disorders implant survival may be lower, and the risk of a compromised peri-implant health and its related complications be greater, but the degree of systemic disease control outweighs the nature of the disorder rather than the risk accompanying dental implant treatment. So, as dental implant treatment is accompanied by significant functional benefits and improved oral health-related quality of life, dental implant therapy is a feasible treatment in almost any medically compromised patient when the required preventive measures are taken and follow-up care is at a high level.

ObjectiveTo assess the validity of ultrasound of major salivary glands (sUS) compared with parotid and labial gland biopsies, sialometry, anti-SSA/Ro antibody status and classification criteria in patients clinically suspected with primary Sjögren’s syndrome (pSS).Methods103 consecutive outpatients with clinically suspected pSS underwent sUS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and clearness of salivary gland border were scored according to the Hocevar scoring system. Total ultrasound score was calculated as the sum of these domains (range 0–48).ResultsAbsolute agreement between sUS and parotid (83%) and labial (79%) gland biopsy outcome was good. Negative sUS predicts negative parotid gland biopsy, and positive sUS predicts positive labial gland biopsy. Compared with the American European Consensus Group (AECG) classification, sUS showed an absolute agreement of 82%, sensitivity of 71% and specificity of 92%. Compared with the American College of Rheumatology (ACR) classification, absolute agreement was 86%, sensitivity was 77% and specificity was 92%. Compared with the ACR-European League Against Rheumatism (EULAR) classification, absolute agreement was 80%, sensitivity was 67% and specificity was 94%. Positive sUS predicts classification, but negative sUS does not exclude classification. The combination of positive sUS with presence of anti-SSA/Ro antibodies or negative sUS with absence of anti-SSA/Ro antibodies showed a high predictive value for classification as pSS or non-pSS.ConclusionIn our prospective inception cohort study derived from daily clinical practice, absolute agreement between sUS and salivary gland biopsies was slightly higher for parotid compared with labial gland biopsies. The combination of positive sUS and presence of anti-SSA/Ro antibodies highly predicts classification according to the AECG, ACR and ACR-EULAR classification criteria.

The oral microbiome of patients with primary Sjogren’s syndrome (pSS) differs from that of healthy individuals.1–3 Whether these changes are the consequence of reduced salivary secretion or specific for pSS is yet unknown. Therefore, the aim of our study was to assess whether patients with pSS have a specific oral microbiome compared with symptom controls (patients without SS, indicated as non-SS patients) and healthy controls (HCs). To capture the overall bacterial composition in the mouth, we collected oral washings instead of buccal swabs from 121 consecutive patients referred for a diagnostic pSS workup and 14 volunteers without oral or ocular dryness (HCs). Patients fulfilling the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria were classified as pSS (n=36) and patients not fulfilling the criteria as non-SS (n=85) (table 1).4 View this table: Table 1 Patient characteristics* Bacterial composition was assessed with 16S rRNA gene sequencing of the V4 region. Reads were processed and diversity was analysed with QIIME V.1.9.1.5 All samples were equated to 8000 reads/sample. Comparative statistics were performed in R V.3.4.2.6 For details see online Supplementary text. ### Supplementary file 1 [SP1.docx] Alpha diversity, that is, the number of bacterial taxa and proportion in which each taxon is represented per sample was measured by the number of observed operational taxonomic units and Shannon index. Alpha diversity was similar between pSS, non-SS and HCs, indicating that oral washings of …

Introduction: When the application of a free vascularised flap is not possible, a segmental mandibular defect is often reconstructed using a conventional reconstruction plate. Mechanical failure of such reconstructions is mostly caused by plate fracture and screw pull-out. This study aims to develop a reliable, mechanically superior, yet slender patient-specific reconstruction plate that reduces failure due to these causes. Patients and Methods: Eight patients were included in the study. Indications were as follows: fractured reconstruction plate (2), loosened screws (1) and primary reconstruction of a mandibular continuity defect (5). Failed conventional reconstructions were studied using finite element analysis (FEA). A 3D virtual surgical plan (3D-VSP) with a novel patient-specific (PS) titanium plate was developed for each patient. Postoperative CBCT scanning was performed to validate reconstruction accuracy. Results: All PS plates were placed accurately according to the 3D-VSP. Mean 3D screw entry point deviation was 1.54 mm (SD: 0.85, R: 0.10–3.19), and mean screw angular deviation was 5.76° (SD: 3.27, R: 1.26–16.62). FEA indicated decreased stress and screw pull-out inducing forces. No mechanical failures appeared (mean follow-up: 16 months, R: 7–29). Conclusion: Reconstructing mandibular continuity defects with bookshelf-reconstruction plates with FEA underpinning the design seems to reduce the risk of screw pull-out and plate fractures.

Introduction: The salivary gland (SG) in primary Sjögren’s syndrome (pSS) is characterized by its lack of function (hyposalivation) and lymphocytic invasion. Small-molecule inhibitors (SMIs) are a new class of drugs, whose diminutive size permits diffusion into cells. SMIs targeting components of the immune system are eagerly being trialed for their potential therapeutic utility in pSS. Neglected until now, however, is a discussion of the potential effects of SMIs on the SG epithelium. Areas covered: We begin by reminding the reader of the SG epithelial compartment, its complicity in inflammatory milieu formation in pSS, and categories of SMIs which merit attention. We discuss each SMI category, including pre-clinical data concerning pSS and likely consequences of their application on the SG epithelium. Expert opinion: Recovery of saliva production in pSS requires restoring the function of the SG epithelium, not solely on inflammation resolution. Many SMIs, for example, those blocking JAK-STAT signaling, interfere with critical epithelial cell pathways, most notably EGF signaling. If the effect of SMIs on SG epithelium is ignored, recovery of SG function will be challenging. We predict that NFκB signaling blockade will impart the least SG epithelium damage whilst reducing inflammation and facilitating recovery from hyposalivation in pSS.

Background Effective systemic treatment is not yet available for primary Sjogren syndrome (pSS). Abatacept (CTLA-4-Ig) targets the CD80/CD86:CD28 co-stimulatory pathway required for full T-cell activation and T-cell dependent activation of B-cells. IV abatacept was shown to be safe, well tolerated, and to decrease disease activity in an open-label study of 15 pSS patients.1 Objectives To assess the efficacy and safety of subcutaneous (SC) abatacept vs. placebo in patients with early active pSS. Methods The Abatacept Sjogren Active Patients phase III (ASAP-III) study is a monocenter, investigator-initiated, double-blind, placebo-controlled trial (NCT02067910). ASAP-III included 80 adult patients with biopsy-proven pSS, fulfilling the AECG and ACR/EULAR criteria, with a disease duration of ≤7 years and moderate to high EULAR Sjogren’s syndrome disease activity score (ESSDAI ≥5). Patients were randomized in a 1:1 ratio to receive weekly SC abatacept (125 mg) or placebo for 24 weeks (figure 1). After the double-blind phase, all patients were treated with abatacept in a 24-week open label phase. Concomitant use of other DMARDs was not permitted, with the exception of a stable dose of prednisone (≤10mg). Rescue therapy with prednisone or cyclophosphamide was permitted after week 12. Participants visited our pSS tertiary referral center nine times, to be evaluated by a multidisciplinary team of rheumatologists, ophthalmologists, and oral and maxillofacial surgeons. The primary endpoint is ESSDAI at 24 weeks. Secondary outcomes over 24 and 48 weeks include clinical, patient reported, functional, histological, laboratory, ultrasound, and microbiome parameters, and the occurrence of (serious) adverse events and treatment discontinuation. Results Baseline characteristics of participants are shown in table 1. Database lock for the blinded stage is planned in March 2019. Subsequently, the first intention-to-treat analyses will be performed, focusing on the ESSDAI and EULAR Sjogren Syndrome Patient Reported Index (ESSPRI), quality of life (EQ-5D), unstimulated and stimulated whole salivary flow (UWS, SWS), Schirmer test, Ocular Staining Score (OSS), serological parameters (RF, IgG), and safety parameters. Conclusion The ASAP-III trial was designed to assess the clinical efficacy and safety of SC abatacept in pSS patients with short disease duration and active disease. The 24-week results will be available during the EULAR congress 2019. Reference [1] Meiners, et al. Ann Rheum Dis2014;73:1393-6. Disclosure of Interests Jolien F. van Nimwegen Speakers bureau: Bristol-Myers Squibb, Greetje S. van Zuiden Speakers bureau: Roche, Suzanne Arends Grant/research support from: Grant/research support from Pfizer, Esther Mossel: None declared, Robin F. Wijnsma: None declared, Alja J. Stel: None declared, Konstantina Delli: None declared, Bert van der Vegt: None declared, Erlin A. Haacke: None declared, Lisette Olie: None declared, Leonie I. Los: None declared, Janita Bulthuis-Kuiper: None declared, Gwenny M. Verstappen: None declared, Sarah A. Pringle: None declared, Fred K.L. Spijkervet: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Roche, Janssen-Cilag, Arjan Vissink: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant for: Roche, Bristol-Myers Squibb, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Bristol-Myers Squibb, Novartis

With great interest we have read the recent publication by Fisher et al ,1 entitled ‘Effect of rituximab on a salivary gland ultrasound score in primary Sjogren’s syndrome: results of the TRACTISS randomised double-blind multicenter substudy’ in which the authors demonstrated a significant improvement in total ultrasound score (TUS) after rituximab treatment compared with placebo at weeks 16 and 48 in 52 patients with primary Sjogren’s syndrome (pSS). We and others have shown that treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, affects the histopathology of the salivary glands and results in a decrease in area of lymphocytic infiltrate in the labial and parotid glands.2–5 This reduction in infiltrated area, that is, up to 50%, is mainly caused by B cell depletion.2 Rituximab treatment also causes a significant loss of germinal centres.2 Interestingly, rituximab treatment also leads to a significant restoration of the ductal epithelium glandular tissue itself. This is illustrated by a significant decrease in number and severity of lymphoepithelial lesions (LELs) in parotid gland tissue 12 weeks after rituximab treatment.2 6 The normalisation of the epithelium appears to be a direct consequence of depletion of intraepithelial B cells.7 Significant improvement of the parotid gland ultrasound score of patients with pSS has been observed before in another randomised controlled trial (RCT) with rituximab, the Tolerance and Efficacy of Rituximab in Primary Sjogren’s Syndrome (TEARS) study.8 This is an RCT with rituximab versus placebo, performed by a French group. Together with the improvement of the histopathology of the gland, it might not be a surprise that Fisher et al 1 also observed a significant improvement in TUS. This newly …

Objective: To assess whether the addition of salivary gland ultrasonography (SGUS) or replacement of current criteria items by SGUS influences the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for primary Sjögren's syndrome. Methods: Included were consecutive patients with complete data on all ACR/EULAR items (n = 243) who underwent SGUS in our primary Sjögren's syndrome expertise center. Clinical diagnosis by the treating physician was used as the gold standard. Separate analyses were performed for patients who underwent labial or parotid gland biopsies. The average score for hypoechogenic areas in 1 parotid and 1 submandibular gland was determined (range 0–3). Next, performance of the ACR/EULAR criteria was evaluated after addition of SGUS or replacement of current items by SGUS. Results: Receiver operating characteristic analysis showed an optimal cutoff value of ≥1.5 for SGUS. The optimal weight for SGUS positivity was 1. Cutoff for ACR/EULAR fulfilment remained ≥4. In patients who underwent a labial gland biopsy (n = 124), the original criteria showed an area under the curve (AUC) of 0.965, sensitivity of 95.9%, and specificity of 92.2%. After the addition of SGUS, the AUC was 0.966, with a sensitivity of 97.3% and specificity of 90.2%. In patients who underwent a parotid gland biopsy (n = 198), similar results were found. Sensitivity of the criteria decreased substantially when SGUS replaced salivary gland biopsy or anti-SSA antibodies, while performance remained equal when SGUS replaced the ocular staining score, Schirmer's test, or unstimulated whole saliva flow. Conclusion: Validity of the ACR/EULAR criteria remains high after incorporation of SGUS. With SGUS, clinicians are offered a larger array of tests to evaluate fulfillment of the ACR/EULAR criteria.

The accuracy of orthognathic surgery has improved with three-dimensional virtual planning. The translation of the planning to the surgical result is reported to vary by >2 mm. The aim of this randomized controlled multi-centre trial was to determine whether the use of splintless patient-specific osteosynthesis can improve the accuracy of maxillary translation. Patients requiring a Le Fort I osteotomy were included in the trial. The intervention group was treated using patient-specific osteosynthesis and the control group with conventional osteosynthesis and splint-based positioning. Fifty-eight patients completed the study protocol, 27 in the patient-specific osteosynthesis group and 31 in the control group. The per protocol median anteroposterior deviation was found to be 1.05 mm (interquartile range (IQR) 0.45-2.72 mm) in the patient-specific osteosynthesis group and 1.74 mm (IQR 1.02-3.02 mm) in the control group. The cranial-caudal deviation was 0.87 mm (IQR 0.49-1.44 mm) and 0.98 mm (IQR 0.28-2.10 mm), respectively, whereas the left-right translation deviation was 0.46 mm (IQR 0.19-0.96 mm) in the patient-specific osteosynthesis group and 1.07 mm (IQR 0.62-1.55 mm) in the control group. The splintless patient-specific osteosynthesis method improves the accuracy of maxillary translations in orthognathic surgery and is clinically relevant for planned anteroposterior translations of more than 3.70 mm.

With great interest we have read the article of Sène et al. (1) in which ectopic germinal centres (GCs) in labial gland biopsies of primary Sjögren syndrome (pSS) patients were found predictive for Non-Hodgkin's lymphoma (NHL) development later in the disease. In the univariate analysis the presence of GCs in these biopsies was not significantly different between pSS patients that developed NHL or pSS patients that did not. This article is protected by copyright. All rights reserved.

Objective\ud \ud A major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.\ud \ud \ud Methods\ud \ud SGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self‐renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.\ud \ud \ud Results\ud \ud SGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS–associated proinflammatory cytokines we induced to proliferate, express senescence‐associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.\ud \ud \ud Conclusion\ud \ud This study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature‐aging phenotype. The knowledge garnered in this study indicates that disease‐modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.

Objectives. Environmental factors in the aetiology of primary Sjogren's syndrome (pSS) are largely unknown. Host-microbiome interaction at mucosal surfaces is presumed to be involved in the aetiopathogenesis of pSS. Here, we assessed whether the microbiome of the buccal mucosa is specific for pSS compared with symptom-controls.Methods. The bacterial composition of buccal swab samples from 37 pSS patients, 86 non-SS sicca patients (with similar dryness symptoms to pSS patients, but not fulfilling the classification criteria) and 24 healthy controls (HCs) was determined with 16S rRNA sequencing. Multivariate Association with Linear Models was used to find associations between individual taxa and pSS, taking into account smoking and dental status. Associations were replicated in a general population cohort (n = 103).Results. The buccal mucosa microbiome of pSS and non-SS sicca patients both differed from HCs. A higher Firmicutes/Proteobacteria ratio was characteristic for both pSS and non-SS sicca patients. Disease status (pSS, nonSS sicca, HCs) and salivary secretion rate contributed almost equally to the variation in bacterial composition between individuals (3.8 and 4.3%, respectively). Two taxa were associated with pSS compared with non-SS sicca patients and 19 compared with HCs. When salivary secretion rate was taken into account, no taxon was associated with pSS compared with non-SS sicca. Twelve of the 19 pSS-associated taxa were correlated with salivary secretion.Conclusion. Dysbiosis of the buccal mucosa microbiome in pSS patients resembles that of symptom-controls. The buccal mucosa microbiome in pSS patients is determined by a combination of reduced salivary secretion and disease-specific factors.

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

Background Primary Sjogren’s syndrome (pSS) patients who exhibit germinal centres (GCs) within salivary gland parenchyma have higher focus scores and present with more disease activity than GC negative pSS patients. Moreover, presence of GCs might be of clinical importance for stratification of treatment. However, there is considerable heterogeneity in reported findings concerning the presence of GCs. This can partially be explained by the difficulty in identifying GCs in diagnostic H and E sections and the lack of uniform histopathological criteria. Objectives The aim of this study was to assess the most appropriate way to identify unequivocally GCs in parotid and labial gland biopsies of pSS patients. Methods As part of routine diagnostic work-up for pSS, both parotid and labial salivary gland biopsies were taken from 100 consecutive patients suspected for pSS. Forty-two patients were classified as having pSS according to the ACR-EULAR criteria, the remaining 58 patients were classified as non-pSS sicca patients. Diagnostic salivary gland biopsies were formalin fixed, paraffin embedded and serially sectioned at 3–4 µm thickness. Sections were stained with H and E as well as immunohistochemically for CD3, CD20, CD21, CD45, Ki67 and Bcl6. Presence of GCs, the number of GCs/mm2 salivary gland parenchyma and level of lymphoid organisation were determined in all sections. Results According to diagnostic H and E staining, in 15% and 2% of pSS patients GCs were present in parotid and labial salivary glands, respectively. Staining for the proliferation marker Ki67 and the GC-B cell associated transcription factor Bcl6, showed higher percentages: 23% and 25%. Much higher percentages of follicular dendritic cell (FDCs) networks were revealed by CD21L (45% and 55%, for parotid and labial glands, respectively) compared to the number of GCs seen in tissue sections stained for Bcl6. Similarly, the median number of CD21+ FDC networks/mm2 was significantly higher than the number of GCs/mm2 as revealed by H and E, Ki67 and Bcl6. Careful evaluation of the consecutive sections stained for CD21L and Bcl6, showed that only roughly half of the FDC networks, also harbour GCs. Finally, not all sections that showed clearly defined GCs by Bcl6 staining, also revealed GCs by Ki67 or H and E staining. Conclusions Due to the difficulty in GC recognition, use of diagnostic H and E leads to an underestimation and incorrect identification of GCs, while using anti-CD21L overestimates GC counts. This suggests that, although CD21+ FDC networks play an essential role in GC development and T/B cell compartmentalization, positivity for CD21+ FDC networks does not always imply presence of ectopic GCs. Furthermore, since Ki67 is an excellent marker for solely the dark zone of GCs, small GCs can be overlooked while other proliferative areas might be mistakenly identified as GCs. This study shows that staining for Bcl6 allows easy and unequivocal identification of GCs and should therefore be implemented in the histopathological evaluation of salivary gland biopsies of pSS patients. Disclosure of Interest None declared

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.

Osteoradionecrosis is defined as bone death secondary to radiotherapy. There is a relationship between the radiation dose received and the occurrence of osteoradionecrosis of the jaws, with the risk increasing above a dose of 60Gy. In cases of class III mandibular osteoradionecrosis, a segmental resection can be indicated. Current practice is to completely remove the affected bone up to the point where the bone looks healthy and is bleeding. Exact resection planning and the use of guided surgery based on imaging of the bone changes have not been reported so far. This article describes a method whereby the radiotherapy dose information is incorporated into the imaging of the affected bone in order to plan a three-dimensional (3D) virtual guided resection and reconstruction of the mandible in osteoradionecrosis. The method enables 3D visualization of each desired dose field in relation to the 3D model of the affected bone. Two types of application - for resection and reconstruction - are described.

Previous studies revealed high incidence of acquired N-glycosylation sites acquired N-glycosylation sites in RNA transcripts encoding immunoglobulin heavy variable region (IGHV) 3 genes from parotid glands of primary Sjogren's syndrome (pSS) patients. In this study, next generation sequencing was used to study the extent of ac-Nglycs among clonally expanded cells from all IGVH families in the salivary glands of pSS patients. RNA was isolated from parotid gland biopsies of five pSS patients and five non-pSS sicca controls. IGHV sequences covering all functional IGHV genes were amplified, sequenced, and analyzed. Each biopsy recovered 1,800-4,000 unique IGHV sequences. No difference in IGHV gene usage was observed between pSS and non-pSS sequences. Clonally related sequences with more than 0.3% of the total number of sequences per patient were referred to as dominant clone. Overall, 70 dominant clones were found in pSS biopsies, compared to 15 in non-pSS. No difference in percentage mutation in dominant clone-derived IGHV sequences was seen between pSS and non-pSS. In pSS, no evidence for antigen-driven selection in dominant clones was found. We observed a significantly higher amount of ac-Nglycs among pSS dominant clone-derived sequences compared to non-pSS. Ac-Nglycs were, however, not restricted to dominant clones or IGHV gene. Most ac-Nglycs were detected in the framework 3 region. No stereotypic rheumatoid factor rearrangements were found in dominant clones. Lineage tree analysis showed in four pSS patients, but not in non-pSS, the presence of the germline sequence from a dominant clone. Presence of germline sequence and mutated IGHV sequences in the same dominant clone provide evidence that this clone originated from a naive B-cell recruited into the parotid gland to expand and differentiate locally into plasma cells. The increased presence of ac-Nglycs in IGHV sequences, due to somatic hypermutation, might provide B-cells an escape mechanism to survive during immune response. We speculate that glycosylation of the B-cell receptor makes the cell sensitive to environmental lectin signals to contribute to aberrant B-cell selection in pSS parotid glands.

Bijwerkingen en interacties van geneesmiddelen kunnen het orofaciale gebied betreffen en varieren van gering tot invaliderend. Een aantal van deze bijwerkingen en interacties wordt in deze bijdrage beschreven, in voorkomende gevallen wordt ook kort het oorzakelijk mechanisme beschreven. Deze opsomming geeft een indruk van de mogelijke bijwerkingen van geneesmiddelen met betrekking tot het orofaciale gebied.

Een groot aantal afwijkingen kan op of in de slijmvliezen van de mond ontstaan. Deze afwijkingen kunnen zich op vele verschillende manieren presenteren. Aan eenzelfde klinische verschijningsvorm kunnen verschillende ziekteprocessen ten grondslag liggen. Een slijmvliesafwijking kan het gevolg zijn van een lokaal proces of een uiting zijn van een gegeneraliseerd ziekteproces. In dit artikel worden de meest voorkomende afwijkingen van de slijmvliezen van de mond gerubriceerd aan de hand van het aspect. Daarnaast wordt een aantal afwijkingen beschreven uitgaande van het mesenchym, bot en de speekselklieren. Ten slotte wordt kort het burning-mouth syndrome besproken.

Salivary gland biopsy is a technique broadly applied for the diagnosis of Sjogren syndrome (SS), lymphoma in SS, and connective tissue disorders (sarcoidosis, amyloidosis). In SS characteristic histology findings are found, including lymphocytic infiltration surrounding the excretory ducts in combination with destruction of acinar tissue. In this article the main techniques are described for taking labial and parotid salivary gland biopsies with respect to their advantages, postoperative complications, and usefulness for diagnostic procedures, monitoring disease progression, and evaluation of treatment.

The aim of this study was to assess the histopathological changes in parotid gland tissue of primary Sjögren's syndrome (pSS) patients treated with abatacept.In all 15 pSS patients included in the open-label Active Sjögren Abatacept Pilot (ASAP, 8 abatacept infusions) study parotid gland biopsies were taken before treatment and at 24 weeks of follow up. Biopsies were analysed for pSS-related histopathological features and placed in context of clini- cal responsiveness as assessed with EULAR Sjögren's syndrome disease activity index (ESSDAI).Abatacept treatment resulted in a decrease of germinal centres (GCs)/ mm2 (p=0.173). Number of GCs/mm2 at baseline was associated with response in the glandular domain of ESSDAI (Spearman ρ=0.644, p=0.009). Abatacept treatment did not reduce focus score, lymphoepithelial lesions, area of lymphocytic infiltrate, amount of CD21+ networks of follicular dendritic cells, and numbers of CD3+ T-cells or CD20+ B- cells. Number of IgM plasma cells/mm2 increased (p=0.041), while numbers of IgA and IgG plasma cells/mm2 were unaffected during abatacept treatment.Abatacept affects formation of GCs of pSS patients in parotid glands, which is dependent on co-stimulation of activated follicular-helper-T-cells. Herewith, local formation of (autoreactive) memory B-cells is inhibited. Presence of GCs at baseline predicts responsiveness to abatacept in the ESSDAI glandular domain.

Total temporomandibular joint replacement is a surgical procedure for patients with severe temporomandibular joint afflictions affecting quality of life, which have not responded beneficially to previous conventional surgery. The aim of this study was to assess the long-term outcome of the Groningen temporomandibular joint (TMJ) prosthesis in patients with chronic pain and mutilated temporomandibular joints following multiple surgical procedures, with respect to prosthesis failure, the patient's postoperative level of satisfaction and longitudinal changes in maximum mouth opening, functional mandibular impairment and pain. Fight female patients were studied in whom Groningen TMJ prostheses were inserted, two unilaterally and six bilaterally.The Groningen TMJ prosthesis was mechanically successful during 8 years of follow-up in seven out of eight patients with a disc dislocation being seen in one patient (7%). Patients were satisfied, despite the limited improvement of the maximum mouth opening, and pain scores.Although the decline of MFIQ scores during 8 years of follow-up was significant compared to baseline (p = 0.027), the effects of the prosthesis on maximum mouth opening, function and pain were limited. This may be due to persistent chronic pain and the adverse effects of multiple previous surgical procedures. (C) 2012 European Association for Cranio-Maxillo-Facial Surgery.

ObjectivesTo assess the persistence of immunoglobulin-producing cell populations in the parotid salivary glands of patients with primary Sjögren's syndrome (pSS) after B cell depletion therapy with rituximab.MethodsThirteen patients with pSS and four control patients were included in this study. Patients with pSS were treated with rituximab or placebo. Sequence analysis was carried out on IgA- and IgG-encoding transcripts extracted from parotid salivary gland biopsy specimens taken before treatment and at 12–16 and 36–52 weeks after treatment.ResultsAt baseline, many clonally related sequences were seen in patients with pSS. The number of clonal expansions was significantly higher in patients with pSS than in control patients. Clonal expansions were composed of IgA- and/or IgG-expressing cells. Rituximab did not significantly alter the degree of clonal expansions. Groups of clonally related cells had members which were shared between biopsy specimens taken before and after treatment. Mutation frequencies of immunoglobulin sequences from clonally related cells in patients with pSS were higher after treatment.ConclusionsRituximab treatment does not alter the characteristic features of increased clonal expansions seen in the parotid salivary glands of patients with pSS. The presence of clonally related immunoglobulin-producing cells before and after rituximab treatment strongly suggests that immunoglobulin-producing cells persist in salivary glands of patients with pSS despite B cell depletion. The presence of mixed isotype expression within groups of clonally related cells indicates local class switching in salivary glands of patients with pSS. Persistent immunoglobulin-producing cells may underlie disease relapse after treatment.

Sjögren's syndrome (SS) is an autoimmune inflammatory disorder of exocrine glands. SS particularly affects the lacrimal and salivary glands. Dry mouth and dry eyes are frequently proffered as presenting symptoms, but nonspecific symptoms such as malaise and fatigue, and extraglandular manifestations like purpura, polyneuropathy and arthritis are also often present. Moreover, lymphomas develop in about 7.5% of SS patients, mostly marginal zone B-cell lymhomas. Futhermore, SS has a very substantial impact on the patients' quality of life and their daily activities. Recently, many breakthroughs have been seen in salivary diagnostics, which not only can be used for diagnosis but also for monitoring of disease activity and disease progression as well as for objectively scoring the effect of intervention treatment with biologicals. In addition, salivary proteomics, genomics and system biology have been shown to be very promising tools in unravelling the pathophysiology of SS, thus providing in depth insight in its underlying mechanisms which could give clues for intervention therapies with biologicals. The latter is of particular interest as B cell depletion therapy has been shown a very promising therapy for a subgroup of SS patients. When applying salivary diagnostics in combination with instruments to rate disease activity and progression in SS, one might be able to select those SS patients who respond to a particular type of biological. These topics are addressed in this review and promises for the near future are described.

PurposeDysphagia (swallowing dysfunction) is a debilitating, depressing, and potentially life-threatening complication in cancer patients that is likely underreported. The present paper is aimed to review relevant dysphagia literature between 1990 and 2010 with a focus on assessment tools, prevalence, complications, and impact on quality of life in patients with a variety of different cancers, particularly in those treated with curative chemoradiation for head and neck cancer.MethodsThe literature search was limited to the English language and included both MEDLINE/PubMed and EMBASE. The search focused on papers reporting dysphagia as a side effect of cancer and cancer therapy. We identified relevant literature through the primary literature search and by articles identified in references.ResultsA wide range of assessment tools for dysphagia was identified. Dysphagia is related to a number of factors such as direct impact of the tumor, cancer resection, chemotherapy, and radiotherapy and to newer therapies such as epidermal growth factor receptor inhibitors. Concomitant oral complications such as xerostomia may exacerbate subjective dysphagia. Most literature focuses on head and neck cancer, but dysphagia is also common in other types of cancer.ConclusionsSwallowing impairment is a clinically relevant acute and long-term complication in patients with a wide variety of cancers. More prospective studies on the course of dysphagia and impact on quality of life from baseline to long-term follow-up after various treatment modalities, including targeted therapies, are needed.

Objective.To retrospectively analyze the clinical course of patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma of the parotid gland and associated Sjögren’s syndrome (SS).Methods.All consecutive patients with SS and MALT lymphoma (MALT-SS) diagnosed in the University Medical Center Groningen between January 1997 and January 2009 were analyzed. Clinical course and treatment outcome of SS and MALT lymphoma were evaluated.Results.From a total of 329 patients with SS, 35 MALT-SS patients were identified, with a median followup of 76 months (range 16–153 mo). MALT lymphoma was localized in the parotid gland in all cases. Treatment consisted of “watchful waiting” (n = 10), surgery (n = 3), radiotherapy (n = 1), surgery combined with radiotherapy (n = 2), rituximab only (n = 13), or rituximab combined with chemotherapy (n = 6). Complete response was observed in 14 patients, partial response in 1 patient, and stable disease in 20 patients. In 6 of 7 patients with initially high SS disease activity (M-protein, cryoglobulins, IgM rheumatoid factor > 100 KIU/l, severe extraglandular manifestations), MALT lymphoma progressed and/or SS disease activity increased after a median followup of 39 months (range 4–98 mo), necessitating retreatment. Only 1 patient with MALT who had low SS disease activity showed progression of lymphoma when left untreated.Conclusion.An initially high SS disease activity likely constitutes an adverse prognostic factor for progression of lymphoma and/or SS. Such patients may require treatment for both MALT lymphoma and SS. In SS patients with localized asymptomatic MALT lymphoma and low SS disease activity, a “watchful waiting” strategy seems justified.

Background: Associations between periodontitis and cardiovascular and autoimmune diseases are most often assessed in patients with a particular cardiovascular or autoimmune disease. To prevent selection bias, this study assesses the existence of associations between periodontitis and cardiovascular and autoimmune diseases in patients attending a dental or periodontal clinic.Methods: Data were collected from 1,276 randomly selected dental records from patients attending a dental (n = 588) or periodontal (n = 688) clinic. Data on the prevalence of cardiovascular and autoimmune diseases were obtained from a validated health questionnaire. Data on the presence of periodontitis were taken from patients' dental records.Results: In uncontrolled analyses, the prevalence of hypertension, diabetes mellitus (DM), and rheumatoid arthritis (RA) is significantly increased in patients with periodontitis. Controlled for confounding, periodontitis was associated with DM, with an odds ratio of 4 (1.03 to 15.3), in the dental clinic. DM was not associated with periodontitis in periodontal clinics. Hypertension does not seem to be associated with periodontitis when controlling for confounders. Periodontitis may be associated with RA in both clinic types.Conclusions: The increased prevalence of cardiovascular and autoimmune diseases among patients with periodontitis attending dental or periodontal clinics may, at least in part, be influenced by confounding. However, the increased prevalence of DM and RA in patients with periodontitis could not be explained by confounding. J Periodontol 2010;81:1622-1628.

This systematic review represents a thorough evaluation of the literature to clarify the impact of cancer therapies on the prevalence, quality of life and economic impact, and management strategies for cancer-therapy-induced trismus. A systematic literature search was conducted with assistance from a research librarian in the databases MEDLINE/PubMed and EMBASE for articles published between January 1, 1990 and December 31, 2008. Each study was independently assessed by two reviewers. Taking into account predetermined quality measures, a weighted prevalence was calculated for the prevalence of trismus. The level of evidence, recommendation grade, and guideline (if possible) were given for published preventive and management strategies for trismus. We reviewed a total of 22 published studies between 1990 and 2008. Most of them assessed the prevalence of this complication, and few focused on management. The weighted prevalence for trismus was 25.4% in patients who received conventional radiotherapy and 5% for the few intensity-modulated radiation therapy studies. No clear guideline recommendations could be made for the prevention or management of trismus. Newer radiation modalities may decrease the prevalence of trismus compared to conventional radiotherapy. Few studies have addressed the quality of life impact of trismus, and no studies were identified to assess the economic impact of trismus. The few preventive and management trials identified in the literature showed some promise, although larger, well-designed studies are required to appropriately assess these therapies before recommendations can be provided.

This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions. Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.

Oral complications are commonly experienced by patients undergoing cancer therapies. The Oral Care Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) has completed nine systematic reviews including Bisphosphonate Osteonecrosis of the Jaw, Odontogenic/Periodontal Infection, Dysgeusia, Oral Fungal Infection, Osteoradionecrosis, Trismus, Oral Pain, Oral Viral Infection, and Xerostomia. The aims of these reviews were to determine the prevalence of each oral complication, relationship with quality of life, economic impact, and formulation of guidelines based on the quality of the literature. The present article described the details of the methodology and statistical analysis utilized in these nine systematic reviews. Additionally, a summary of the quality of the literature from these oral complications is presented. Oral complications associated with cancer therapies are common among cancer patients. The systematic reviews by the Oral Care Study Group of MASCC/ISOO provide a thorough assessment of the available literature for these oral complications.

The purpose was to review relevant scientific papers written since 1989 which focused on the prevalence and management of dysgeusia as an oral side effect of cancer treatment. Our literature search was limited to English language papers published between 1990 and 2008. A total of 30 papers were reviewed; the results of 26 of these papers were included in the present systematic review. A structured assessment form was used by two reviewers for each paper. Studies were weighted as to the quality of the study design, and treatment recommendations were based on the relative strength of each paper. A wide range in reported prevalence of dysgeusia was identified with the weighted prevalence from 56–76%, depending on the type of cancer treatment. Attempts to prevent dysgeusia through the prophylactic use of zinc sulfate or amifostine have been of limited benefit. Nutritional counseling may be helpful to some patients in minimizing the symptoms of dysgeusia. Dysgeusia is a common oral side effect of cancer therapy (radiotherapy, chemotherapy, or combined modality therapy) and often impacts negatively on quality of life. From the current literature, there does not appear to be a predictable way of preventing or treating dysgeusia.