Chronic Periodontal Infection and Not Iatrogenic Interference Is the Trigger of Medication-Related Osteonecrosis of the Jaw: Insights from a Large Animal Study (PerioBRONJ Pig Model).

Background and Objectives: Antiresorptive drugs are widely used in osteology and oncology. An important adverse effect of these drugs is medication-induced osteonecrosis of the jaw (MRONJ). There is scientific uncertainty about the underlying pathomechanism of MRONJ. A promising theory suspects infectious stimuli and local acidification with adverse effects on osteoclastic activity as crucial steps of MRONJ etiology. Clinical evidence showing a direct association between MRONJ and oral infections, such as periodontitis, without preceding surgical interventions is limited. Large animal models investigating the relationship between periodontitis and MRONJ have not been implemented. It is unclear whether the presence of infectious processes without surgical manipulation can trigger MRONJ. The following research question was formulated: is there a link between chronic oral infectious processes (periodontitis) and the occurrence of MRONJ in the absence of oral surgical procedures? Materials and Methods: A minipig large animal model for bisphosphonate-related ONJ (BRONJ) using 16 Göttingen minipigs divided into 2 groups (intervention/control) was designed and implemented. The intervention group included animals receiving i.v. bisphosphonates (zoledronate, n = 8, 0.05 mg/kg/week: ZOL group). The control group received no antiresorptive drug (n = 8: NON-ZOL group). Periodontitis lesions were induced by established procedures after 3 months of pretreatment (for the maxilla: the creation of an artificial gingival crevice and placement of a periodontal silk suture; for the mandible: the placement of a periodontal silk suture only). The outcomes were evaluated clinically and radiologically for 3 months postoperatively. After euthanasia a detailed histological evaluation was performed. Results: Periodontitis lesions could be induced successfully in all animals (both ZOL and NON-ZOL animals). MRONJ lesions of various stages developed around all periodontitis induction sites in the ZOL animals. The presence of MRONJ and periodontitis was proven clinically, radiologically and histologically. Conclusions: The results of this study provide further evidence that the infectious processes without prior dentoalveolar surgical interventions can trigger MRONJ. Therefore, iatrogenic disruption of the oral mucosa cannot be the decisive step in the pathogenesis of MRONJ.

The influence of the SARS-CoV-2 pandemic on oral and maxillofacial surgery: a nationwide survey among 54 hospitals and 240 private practices in Germany.

OBJECTIVE: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has created hitherto unknown challenges for healthcare systems and patient care. This study aimed to analyze its influence on patient care and healthcare management in oral and maxillofacial surgery (OMFS) in Germany. MATERIALS AND METHODS: A nationwide survey of the German Association of Oral and Maxillofacial Surgery was performed. Individual questionnaires containing 10 questions for university as well as non-university hospitals and 15 questions for private practices (PPs) for OMFS were created to collect data for patient numbers and surgical procedures conducted, usage of personal protection equipment (PPE), SARS-CoV-2 tests, and economic aspects. RESULTS: Fifty-four hospitals and 240 PPs participated in the study. The reduction in ward capacities and number of surgical procedures ranged from 17 to 78%. PPE consisted of standard surgical masks (58% hospitals, 64% PPs) and FFP2/N95/KN95 respirators (45% hospitals, 48% PPs). Preoperative SARS-CoV-2 tests were more frequently performed in hospitals (34% vs 2%). At PPs, turnover for medical and dental procedures billed to the public insurance had reduced to 58.81% and 62.43%, respectively, of the corresponding values for 2019, and 58.75% of the PPs had applied for short-time allowances. CONCLUSION: With the exception of some elective procedures, primary patient care in OMFS has been assured during the pandemic. However, the immense economic burden on hospitals and PPs cannot be conclusively assessed at this point. CLINICAL RELEVANCE: For OMFS, the German healthcare system has shown the ability to adapt to emergency situations such as the SARS-CoV-2 pandemic. Adequate surgical capacities in OMFS are necessary even during pandemics.

Infection as an Important Factor in Medication-Related Osteonecrosis of the Jaw (MRONJ).

Medication-related osteonecrosis of the jaw (MRONJ) has become a well-known side effect of antiresorptive, and antiangiogenic drugs commonly used in cancer management. Despite a considerable amount of literature addressing MRONJ, it is still widely accepted that the underlying pathomechanism of MRONJ is unclear. However, several clinical and preclinical studies indicate that infection seems to have a major role in the pathogenesis of MRONJ. Although there is no conclusive evidence for the infection hypothesis yet, available data have shown a robust association between local infection and MRONJ development. This observation is very critical in order to implement policies to reduce the risk of MRONJ in patients under antiresorptive drugs. This critical review was conducted to collect the most reliable evidence regarding the link between local infection and MRONJ pathogenesis.

[IMMUNOTHERAPY WITH CHECKPOINT INHIBITORS (ICPI) AND IMMUNE RELATED ADVERSE EVENTS (IRAE'S)].

INTRODUCTION: In recent years, considerable progress has been achieved in understanding the interaction between malignant cells and immune cells. The immune system continually seeks out and destroys mutated cells, but in some cases, mutations may occur and give some malignant cells the advantage to neutralize and evade the immune system. One of the regulatory mechanisms that allows these cells to abrogate immune responses is based on Immune Checkpoints. These checkpoints include the Cytotoxic-T lymphocyte antigen-4 (CTLA-4), Programmed cell death protein-1 (PD-1) and its ligand Programmed death-ligand-1 (PD-L1). Tasuku Honjo and James Allison, 2018 Nobel Prize laureates, investigated various components of these mechanisms. They found that in some cases malignant cells may overexpress binding sites that interact with CTLA-4 or PD-1, like the PD-L1 molecule, thus managing to maneuver the immune system. They paved the way for a new class of cancer drugs by showing different strategies to disrupt these checkpoints. This understanding has prompted a paradigm shift in oncology and a breakthrough in the development of new generation immunotherapy drugs: Immune Checkpoint Inhibitors (ICPi). By unbalancing the immune system, these treatments also generated dysimmune toxicities, called Immune Related Adverse Events (irAEs). The study of irAEs is in its infancy; there are very few prospective studies. Where possible, the estimates of irAE incidence were drawn from meta-analyses of randomized controlled trials. In this article, we discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; the impact of autoimmune manifestations on cancer outcome and management of irAEs.

Interdisciplinary full-mouth rehabilitation for redefining esthetics, function, and orofacial harmony.

OBJECTIVE: In severe congenital or acquired orofacial anomalies, both dental esthetics and function are usually compromised. In particular, the esthetic ideas of the final desired appearance may differ from patient to patient, as the human esthetic sensibility differs significantly. Especially in complex cases, digital technology today offers outstanding improvements and simplifications in craniomaxillofacial surgical and prosthetic treatments, leading to a wide range of planning and pretreatment options. CLINICAL CONSIDERATIONS: This case report describes a patient-oriented interdisciplinary craniomaxillofacial surgical and prosthetic treatment with noninvasive tooth-colored splints, a Le Fort I osteotomy, and a full-mouth rehabilitation to meet the patient's demand for better function as well as orofacial esthetics and harmony. CONCLUSIONS: By means of the digitally planned Le Fort I intervention and completion of the prosthetic rehabilitation, it was possible to optimize esthetics and facial harmony. CLINICAL SIGNIFICANCE: In complex cases, digital technology today offers outstanding improvements and simplifications in craniomaxillofacial surgery and prosthetic treatments, leading to a wide range of planning and pretreatment options. Computer-aided design/computer-aided manufacturing technology enables the fabrication of tooth-colored flexible polycarbonate splints that offer a noninvasive, removable, functional, and esthetic solution. In intricate cases involving craniomaxillofacial anomalies, often together with necessary orofacial surgeries or prosthetic treatments due to moderate to severe tooth wear, such digital preprosthetic treatment and planning options represent an important enhancement with more predictable results.

What Factors Are Associated With Regional Recurrence After Operative Treatment of Oral Squamous Cell Carcinoma?

PURPOSE: A considerable proportion of oral squamous cell carcinoma (OSCC) recurrences involve the neck, which has a substantial impact on prognosis and is poorly understood. The purpose of this study was to analyze clinical and pathologic characteristics of regional recurrence of OSCC and identify possible risk factors. MATERIALS AND METHODS: A single-center retrospective cohort study was designed to address the study purpose. All patients who were treated surgically for primary OSCC with or without adjuvant therapy between 2010 and 2015 were considered for inclusion with respect to predefined criteria, and demographic, clinical, and pathologic variables were collected. The lymph node status after primary OSCC treatment (pN) was defined as the predictor variable, and the occurrence of regional recurrence served as the primary outcome variable. Further variables of special interest were the histologic differentiation (G status) of the primary OSCC and the values of the lymph node ratio and log odds of positive lymph nodes. Descriptive, inferential, and appropriate time-dependent (Kaplan-Meier analysis, Cox regression model) statistics were computed. The level of statistical significance was set at P ≤ .05. RESULTS: The study sample was composed of 171 patients (70 women and 101 men; average age, 62.4 years). Neck failure occurred in 18 patients (11%) either in combination with local recurrence (15 patients) or in isolation (3 patients). Poor histologic differentiation of the primary tumor was identified as an independent risk factor for regional recurrence. Most neck recurrences manifested in previously unaddressed levels (IV and V). CONCLUSIONS: Regional recurrence of OSCC might be associated with specific clinicopathologic parameters of the primary tumor. The importance of these parameters for OSCC prognosis assessment and recurrence prediction should be elucidated in further studies.

Comorbidity Assessment in Patients With Oral Squamous Cell Carcinoma: Can Imaging Techniques (Fludeoxyglucose Positron-Emission Tomographic Computed Tomography and Contrast-Enhanced Computed tomography) Provide Additional Information?

PURPOSE: This study evaluated the role of imaging staging examinations (positron-emission tomographic computed tomography [PET/CT] and contrast-enhanced computed tomography [ceCT]) for the assessment of the comorbidity status of patients with oral squamous cell carcinoma (OSCC). A binary null hypothesis was drafted: 1) imaging staging examinations do not augment knowledge about the comorbidity status of patients with OSCC and 2) there is no difference between PET/CT and ceCT in this regard. MATERIALS AND METHODS: A retrospective cohort study design was selected to address the research question. Patients with histologically confirmed OSCC who underwent whole-body staging by PET/CT or ceCT from 2012 through 2015 were considered for inclusion according to predefined criteria. Data collection was performed by the review of patient charts and histology, radiology, and nuclear medicine reports. The Charlson Comorbidity Index (CCI) was chosen to quantify comorbidity and was calculated before and after staging and then compared. The type of imaging staging examination (PET/CT or ceCT) served as the predictor variable and the CCI was determined as the primary outcome variable. Descriptive and inferential statistics were computed for the variable scale. The significance level was set at a P value less than or equal to .05. RESULTS: The sample was composed of 178 patients (71 women, 107 men; average age, 64.2 yr) of whom 109 (61%) underwent PET/CT and 69 (39%) underwent ceCT staging. The pre- and post-staging CCI notably differed. Neither imaging technique showed superior results. CONCLUSION: Relevant and otherwise covert comorbidities can be found by the performance of imaging staging examinations. This enables clinicians to better assess the peri-therapeutic risk and prognosis of patients with OSCC. Therefore, a detailed evaluation of incidental findings on imaging studies is warranted and recommended.

Shifting cancer care towards Multidisciplinarity: the cancer center certification program of the German cancer society.

BACKGROUND: Over the last decades numerous initiatives have been set up that aim at translating the best available medical knowledge and treatment into clinical practice. The inherent complexity of the programs and discrepancies in the terminology used make it difficult to appreciate each of them distinctly and compare their specific strengths and weaknesses. To allow comparison and stimulate dialogue between different programs, we in this paper provide an overview of the German Cancer Society certification program for multidisciplinary cancer centers that was established in 2003. MAIN BODY: In the early 2000s the German Cancer Society assessed the available information on quality of cancer care in Germany and concluded that there was a definite need for a comprehensive, transparent and evidence-based system of quality assessment and control. This prompted the development and implementation of a voluntary cancer center certification program that was promoted by scientific societies, health-care providers, and patient advocacy groups and based on guidelines of the highest quality level (S3). The certification system structures the entire process of care from prevention to screening and multidisciplinary treatment of cancer and places multidisciplinary teams at the heart of this program. Within each network of providers, the quality of care is documented using tumor-specific quality indicators. The system started with breast cancer centers in 2003 and colorectal cancer centers in 2006. In 2017, certification systems are established for the majority of cancers. Here we describe the rationale behind the certification program, its history, the development of the certification requirements, the process of data collection, and the certification process as an example for the successful implementation of a voluntary but powerful system to ensure and improve quality of cancer care. CONCLUSION: Since 2003, over 1 million patients had their primary tumors treated in a certified center. There are now over 1200 sites for different tumor entities in four countries that have been certified in accordance with the program and transparently report their results from multidisciplinary treatment for a substantial proportion of cancers. This led to a fundamental change in the structure of cancer care in Germany and neighboring countries within one decade.

Is There Evidence for the Presence and Relevance of the PD-1/PD-L1 Pathway in Oral Squamous Cell Carcinoma? Hints From an Immunohistochemical Study.

PURPOSE: To examine oral squamous cell carcinoma (OSCC) specimens for programmed death ligand-1 (PD-L1) expression and presence of programmed death-1 (PD-1)-positive tumor-infiltrating lymphocytes (TILs) and to determine possible clinicopathologic implications. It was hypothesized that PD-L1 expression and PD-1-positive TIL presence in OSCC would have no clinical relevance. MATERIALS AND METHODS: The authors implemented a retrospective cohort study design. The study cohort was chosen in compliance with predefined inclusion criteria. Demographic, clinical, and histopathologic data were gathered. Tissue microarrays were obtained from paraffin-embedded OSCC specimens and analyzed immunohistochemically for PD-L1 expression and PD-1-positive TIL infiltration. PD-L1 positivity of OSCC specimens served as the predictor variable and neck node metastasis served as the primary outcome variable. Descriptive and inferential statistics were computed and the significance level was set at a P value less than or equal to .05. RESULTS: The study sample was composed of 88 patients (48 men, 40 women; mean age, 61.34 yr). Marked PD-L1 expression was detected in 29% of OSCC specimens (26 of 88) and 83% of specimens (73 of 88) exhibited a high rate of PD-1-positive TIL infiltration. PD-L1 positivity of OSCC samples was significantly associated with the anatomic origin of OSCC (P = .039), presence of cervical metastasis (P = .039), and high PD-L1-positive TIL infiltration (P = .033). CONCLUSION: A considerable proportion of OSCCs exhibited marked PD-L1 expression. This could be associated with clinical parameters. PD-L1 expression in OSCC might differ depending on its anatomic origin. PD-1-positive TILs could be detected in most OSCC specimens. These findings might indicate a potential role for the PD-1 and PD-L1 pathway in OSCC.

Photodynamic Inactivation of Actinomyces naeslundii in Comparison With Chlorhexidine and Polyhexanide--A New Approach for Antiseptic Treatment of Medication-Related Osteonecrosis of the Jaw?

PURPOSE: Local antimicrobial therapy is a fundamental principle in the treatment of lesions of medication-related osteonecrosis of the jaw. Antimicrobial photodynamic therapy (aPDT) as a local application for the treatment of microbial infections has become more widely used in recent years. In the mouth, the bone surface is in constant contact with saliva and thus cannot be kept sterile, making the development of strategies for disinfection even more important. Different methods currently in use include local rinses with chlorhexidine (CHX), polyhexanide (PHX), or aPDT. This study compared the efficiency of these 3 methods. MATERIALS AND METHODS: The in vitro activity of 3 different agents against slowly growing Actinomyces naeslundii isolated from a patient with osteonecrosis was evaluated. PHX 0.04% solution, CHX 0.12% solution, and methylene blue (MB) based dye with a laser light of 660-nm wavelength (aPDT) were compared. RESULTS: The decrease in colony-forming units by each method was measured using an in vitro killing assay based on a water-exposed surface in a well plate. MB dye with laser (10 seconds) decreased the bacterial load by more than 4 orders of magnitude and was superior to PHX and CHX exposure for 60 seconds. CONCLUSION: Laser exposure alone and MB dye exposure alone decreased bacterial loads slightly, but less efficiently than 60-second exposure to PHX or CHX. The most effective means of decreasing colony-forming units was achieved by a combination of laser light and dye, which also can be used clinically.

Computer-Assisted Designed and Manufactured Procedures Facilitate the Lingual Application of Mandible Reconstruction Plates.

PURPOSE: Lingual positioning of mandible reconstruction plates can prevent typical complications such as plate exposure and orocutaneous fistulas. The aim of this study was to evaluate the feasibility and clinical outcomes of lingually applied patient-specific reconstruction plates. MATERIALS AND METHODS: A retrospective cohort study of patients managed with reconstruction plates positioned at the lingual side of the mandible was performed. The following outcome variables were analyzed: feasibility and handling of the lingual application, fitting accuracy, and postoperative complications. RESULTS: The study sample included 8 patients (4 women, 4 men) with a mean age of 68.8 years (range, 43 to 79 yr). The indications for plate use were defect-like zones owing to multiple fractures in the atrophic mandible (n = 2) and segmental defects attributed to squamous cell carcinoma, osteomyelitis, and bisphosphonate-related osteonecrosis (n = 6). Off-the-shelf reconstruction plates, which were intraoperatively bent (n = 2) or pre-bent to a stereolithographic model (n = 1), or fully computer-assisted designed and computer-assisted manufactured (CAD/CAM) patient-specific reconstruction plates (n = 5) were used. Lingual application of reconstruction plates was feasible in all cases and considerably facilitated by the CAD/CAM plates. The fitting accuracy was high. Within an average follow-up period of 15.3 months, no loosening of plates or screws, plate fracture, or orocutaneous fistula occurred and no dysphagia was observed with the exception of 1 case, in which plate exposure was due to extreme soft tissue thinning and tumor recurrence. CONCLUSIONS: Lingual application of CAD/CAM patient-specific reconstruction plates is technically feasible with high accuracy. It has great potential for low complication rates, especially in unfavorable soft tissue conditions.

Are There Clinical or Pathological Parameters of Maxillary Oral Squamous Cell Carcinoma With an Influence on the Occurrence of Neck Node Metastasis? An Appraisal of 92 Patients.

PURPOSE: To determine the proportion of patients with cervical metastases caused by maxillary oral squamous cell carcinoma (OSCC) and to identify any clinical or pathologic parameters that might be associated with the occurrence of metastatic neck disease. MATERIALS AND METHODS: A retrospective cohort study of all patients managed with primary surgical resection of maxillary OSCC at the authors' institution from 2006 through 2013 was performed. Cervical lymph node dissection and adjuvant therapy were performed as warranted by preoperative staging examinations or histopathologic evaluation or as recommended after multidisciplinary consultation, and regular follow-up protocols were followed. In this analysis, each maxillary OSCC was assigned to an anterior or a posterior anatomic group based on the location of the primary lesion, with the anatomic tumor location serving as the predictor variable and the occurrence of cervical lymph node metastases as the outcome variable. Descriptive and inferential statistics were calculated with a significance level set at a P value less than .05 and post hoc power analyses were performed. RESULTS: The study sample was composed of 92 patients (38 women, 54 men; average age, 60.9 yr). Overall, 27 patients developed cervical metastases (29.3%). Neck disease was present in 15 patients (16.3%) at initial presentation. Delayed cervical metastases were diagnosed in 12 patients (13%) and manifested after an average period of 11.17 months. The anatomic location of the OSCC within the maxillary structures (anterior vs posterior) and the histologic grade greatly influenced the occurrence of metastatic neck disease. No associations were found for the variables tumor size and resection status. CONCLUSION: In this series, cervical lymph node metastases were frequent and to some degree predictable based on anatomic location and tumor grade.

Silicone implants and lymphoma: The role of inflammation.

The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren's syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein-Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1). A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma. We suggest that patients with an inflammatory response against silicone implants be monitored carefully.

Vascular endothelial growth factor receptor isoforms: are they present in oral squamous cell carcinoma?

PURPOSE: Although the clinical importance of vascular endothelial growth factor (VEGF) overexpression in oral squamous cell carcinoma (OSCC) has been investigated, there are limited data about the overexpression of VEGF receptors (VEGF-Rs) and their clinical importance. VEGF-R isoforms have proven influence on proliferation rates, metastasis, and survival in different neoplasms. This study was conducted to investigate VEGF-R expression levels in OSCC samples and to identify any clinical relevance. MATERIALS AND METHODS: A retrospective cohort study design (n = 50) was used. Clinical data were gathered from patient charts. Validated immunohistochemical methods were applied to determine VEGF-R isoform expression by tumor cells. Descriptive and inferential statistics with respect to the variable scale were computed. The significance level was set at a P value less than or equal to .05. RESULTS: This study found overexpression of different VEGF-R isoforms in 88% of examined specimens. Statistically important associations were detected between overexpression of specific VEGF-Rs and tumor size, neck node metastasis, and tumor-associated death. Furthermore, a history of common OSCC risk factors (smoking and alcohol consumption) were found considerably more often in patients whose OSCC specimens displayed VEGF-R overexpression. CONCLUSION: These findings show that VEGF-R overexpression occurs frequently in OSCC and could have clinical implications.

Maxillofacial Fractures: Midface and Internal Orbit-Part I: Classification and Assessment.

Fractures of the midface and internal orbit occur isolated or in combination with other injuries. Frequently, the patients are first seen in emergency rooms responsible for the coordination of initial diagnostic procedures, followed by the transfer to specialties for further treatment. It is, therefore, important for all physicians treating facial trauma patients to understand the basic principles of injuries to the midface. Thus, this article aims to describe the anatomy and the current classification systems in use, the related clinical symptoms, and the essential diagnostic measures to obtain precise information about the injury pattern.

Maxillofacial Fractures: Midface and Internal Orbit-Part II: Principles and Surgical Treatment.

Current clinical assessment and imaging techniques were described in part 1, and this article presents a systematic review of the surgical treatment principles in the management of midface and internal orbit fractures from initial care to definitive treatment, including illustrative case examples. New developments enabled limited surgical approaches by standardization of osteosynthesis principles regarding three-dimensional buttress reconstruction, by newly developed individualized implants such as titanium meshes and, especially for complex fracture patterns, by critical assessment of anatomical reconstruction through intraoperative endoscopy, as well as intra- and postoperative imaging. Resorbable soft tissue anchors can be used both for ligament and soft tissue resuspension to reduce ptosis effects in the cheeks and nasolabial area and to achieve facial aesthetics similar to those prior to the injury.

Conservative management of medication-related osteonecrosis of the maxilla with an obturator prosthesis.

Advanced maxillary medication-related osteonecrosis of the jaw can cause extensive hard and soft tissue destruction that results in long-term oroantral fistulae. The surgical treatment of medication-related osteonecrosis of the jaw may relieve acute symptoms and eliminate the signs of inflammation, but the primary and sustained plastic closure of these defects can challenge both the clinician and the patients. Although the use of obturator prostheses for maxillary defects after ablative oncologic surgery is well documented, studies about this treatment for similar medication-related osteonecrosis of the jaw-related defects are missing. This presentation of clinical situations describes the use of obturators as a conservative alternative to repetitive surgery for the rehabilitation of selected maxillary defects with oroantral communications.

Infection and autoimmunity in Sjogren's syndrome: a clinical study and comprehensive review.

Sjögren's syndrome (SS) is an autoimmune disease characterized primarily by lymphocytic infiltration of the exocrine glands, and autoantibody production. Multiple environmental factors affecting an individual with a genetic susceptibility may trigger the development of SS. Herein, we aimed to evaluate links between the different pebbles in the mosaic of SS. Demographic, clinical data and blood samples were gathered from 82 consecutive patients with SS, and 139 healthy controls. Samples were analyzed for infectious serology and auto-antibodies as well as for relevant genetic mutations (TAP genes) and cytokines levels. An immune response (IgG) against Epstein-Barr virus (EBV) early antigen (EA) was positively associated with SS (OR 4; 95% CI: 1.82-8.83, p = 0.001) while a protective effect of IgG anti-cytomegalovirus (CMV) was observed (OR 0.3; 95%CI: 0.16-0.74, p = 0.009). Anti-Ro/SSA, anti-LA/SSB, anti-nuclear, anti-gliadin, anti-TTG-IgG and anti-RNP antibodies were statistically more prevalent among SS patients than controls. Notably, the presence of anti-Ro/SSA and anti La/SSB correlated with anti-EBVEA IgG (OR 3.1; 95%CI: 1.08-8.74) and (OR 3.9; 95%CI: 1.37-10.96) respectively. Autoantibodies, cytokines and several genetic markers correlated with clinical manifestation of SS. Our data suggest that infectious agents may play both a causative and protective role in the pathogenesis of SS. Moreover certain autoantibodies, cytokines and specific TAP alleles correlate with clinical manifestations of SS, and may enable better prediction and/or directed therapy once confirmed in future studies.