Salivary Cytokines Research Articles

Correlation of Serum and Salivary Cytokines Level With Clinical Parameters in Metabolic Syndrome With Periodontitis.

Metabolic Syndrome (MS) and chronic oral condition (periodontitis [PD]) are state of inflammation. The study was conducted to determine alterations in serum and salivary cytokines level in MS and/or chronic PD in the North Indian population. This cross-sectional study carried out in northern part of India. The study subjects of similar ethnicity were recruited according to International Diabetes Federation (IDF) criteria for MS, while chronic PD was diagnosed on the basis of packet depth and clinical attachment level. ELISA method was employed to assess cytokine level. All subjects were divided in four groups Gr A (MS + PD), B (MS), C (PD), and a control Gr D. The serum and salivary tumor necrosis factor alpha (TNF-α) level in Gr A, B, and C was significantly higher than Gr D (P<0.05). Serum interleukin-10 (IL-10) level in Gr A, B, and C was lower than Gr D (P<0.05), but this difference was not significant between Gr C and Gr D. Serum IL-10 level in Gr A was significantly lower than Gr C (P<0.05). Salivary IL-10 level was not significantly altered in any group. Proinflammatory marker TNF-α has correlation with clinical parameters in patients of MS having PD. The study suggests level of salivary TNF-α may be utilized as a surrogate marker of MS and PD.

Salivary cytokines as biomarkers of periodontal diseases.

Research into biomarkers of periodontitis is driven by mainly three targets: to identify 'at risk' patients before periodontal tissue destruction occurs; to determine disease activity and progression; and to build up our understanding of this complex disease with the purpose of finding new therapeutic targets. Whilst blood and gingival crevicular fluid were previously the biological samples of choice, saliva has recently gained more attention as a readily accessible oral fluid which has a mediator profile similar to that of serum and gingival crevicular fluid. The aim of this paper was to give a comprehensive overview of salivary cytokines in periodontitis, highlighting extensively studied cytokines such as interleukin-1beta and interleukin-6, but also cytokines that have been the subject of only a few studies and which warrant further investigation. Cross-sectional and longitudinal studies of salivary cytokines, and the potential of cytokines as periodontitis biomarkers, are evaluated. Finally, a discussion of potential confounding factors, such as concurrent systemic diseases and smoking, is presented.

Childhood Adversity and Chronic Stress Influence Vagal Tone and the Proinflammatory Response to Acute Stress in Women with Breast Cancer

We previously reported that women diagnosed with breast cancer exhibit a proinflammatory phenotype (increased behavioral symptoms and higher IL-6 levels), if exposed to childhood adversity. The purpose of this project was to determine if childhood adversity and/or chronic stress influenced vagal tone, the cortisol response, and the proinflammatory response to the Trier Social Stress Test (TSST), in women recently diagnosed with breast cancer. We hypothesized that exposure to child adversity and/or chronic stress will suppress the vagal anti-inflammatory pathway, increasing risk for greater stress-associated production of proinflammatory cytokines. Women were assessed for chronic stress and childhood adversity and completed the TSST while wearing Holter monitors to capture vagal tone. Salivary cortisol and cytokines were measured before, throughout, and after the TSST. Results revealed that women reporting greater childhood emotional abuse and neglect or chronic stress had lower vagal tone during the TSST and greater levels of cortisol and IL-6 post-TSST. Emotional neglect was associated with an exaggerated IL-6 response, while physical neglect was related to greater IL-1 beta response to the TSST. Women with greater chronic stress had higher IL-6 and IL-1 beta post-TSST. These results demonstrate that women with breast cancer exposed to greater childhood adversity and chronic stress exhibit a more intense stress-induced proinflammatory response, which may be mediated by suppression of vagal tone.

Associations among Inflammatory Biomarkers in the Circulating, Plasmatic, Salivary and Intraluminal Anatomical Compartments in Apparently Healthy Preschool Children from the Western Highlands of Guatemala.

BackgroundUndernutrition and inflammation are related in many ways; for instance, non-hygienic environments are associated with both poor growth and immunostimulation in children.ObjectiveTo describe any existing interaction among different inflammation biomarkers measured in the distinct anatomical compartments of whole blood, feces, plasma and saliva.MethodsIn this descriptive, cross-sectional study, samples of whole blood, feces, plasma and saliva were collected on the 8th and last week of observation among 87 attendees (42 girls and 45 boys) of 3 daycare centers offering a common 40-day rotating menu in Guatemala’s Western Highlands. Analyses included white blood cell count (WBC), fecal calprotectin, and plasmatic and salivary cytokines including IL-1B, IL-6, IL-8, IL-10 and TNF-α. Associations were assessed using Spearman rank-order and goodness-of-fit correlations, as indicated, followed by backwards-elimination multiple regression analyses to determine predictor variables for IL-10 in both anatomical compartments.ResultsOf a total of 66 cross-tabulations in the Spearman hemi-matrix, 22 (33%) were significantly associated. All 10 paired associations among the salivary cytokines had a significant r value, whereas 7 of 10 possible associations among plasma cytokines were significant. Associations across anatomical compartments, however, were rarely significant. IL-10 in both biological fluids were higher than corresponding reference values. When a multiple regression model was run in order to determine independent predictors for IL-10 in each anatomical compartment separately, IL-6, IL-8 and TNF-α emerged as predictors in plasma (r2 = 0.514) and IL-1B, IL-8 and TNF-α remained as independent predictors in saliva (r2 = 0.762). Significant cross-interactions were seen with WBC, but not with fecal calprotectin.ConclusionInteractions ranged from robust within the same anatomical compartment to limited to nil across distinct anatomical compartments. The prominence of the anti-inflammatory cytokine, IL-10, in both plasma and saliva is consistent with its counter-regulatory role facing a broad front of elevated pro-inflammatory cytokines in the same compartment.

Salivary Immunosuppressive Cytokines IL-10 and IL-13 Are Significantly Elevated in Oral Squamous Cell Carcinoma Patients

Oral squamous cell carcinoma (OSCC) is considered to be one of the most fatal diseases worldwide, owing to its late diagnosis and lack of availability of established reliable biomarkers. The aim of this study was to highlight the significance of immunosuppressive cytokines as potential biomarkers in OSCC. Whole unstimulated saliva was collected from each individual (30 OSCC patients and 33 age- and gender-matched healthy controls). Immunosuppressive cytokines, including IL-4, IL-10, IL-13, and IL-1RA, were evaluated in each sample using Luminex multianalyte profiling (xMAP) technology on BioPlex instrument. Our results showed that all the studied salivary cytokines were raised in OSCC patients as compared to controls, where IL-10 and IL-13 salivary levels showed statistically significant difference (p = .004 and p = .010, respectively). Mean levels of salivary cytokines in three histologically defined OSCC categories, compared employing one-way ANOVA, showed that salivary levels of IL-1RA were highest in patients having poorly differentiated OSCC tumors as compared to those having moderately and well-differentiated tumors (p = .000 and p = .002, respectively). Among OSCC individuals, duration of smokeless tobacco correlated positively with IL-1RA (p = .036). We conclude that salivary levels of immunosuppressive cytokines, IL-4, IL-10, IL-13, and IL-1RA, could prove to be potential biomarkers of OSCC and can be further investigated as markers of early detection and disease progression.

Recent Advances in Clinical Immunology, Endocrine &amp; Metabolic Drugs: An Editorial Overview

An analytical review of the articles published in the two issues of Clinical Immunology Endocrine Metabolic Drugs (volume 1, 2014) is reported. Various topics are covered in volume 1 of the journal. Clinical Immunology is represented in six articles related to nickel hypersensitivity (2 articles), therapeutic approaches in human tuberculosis, immune biomarkers in trauma patients, salivary cytokines in normal weight children and oral sensitization in rats. Endocrinology is the main topic of the two articles dealing with polycystic ovary syndrome and androgen receptor antagonists in prostate cancer. The vascular pathophysiology is the major theme of two papers dealing with the role of angiotensin II and post-prandial oxidative burst. Finally, a paper is devoted to antibiotics resistance of four probiotics. Keywords: Clinical immunology, endocrinology, metabolism, drug targets.

Psychiatric Symptoms, Salivary Cortisol and Cytokine Levels in Young Marijuana Users.

Psychological maturation continues into young adulthood when substance abuse and several psychiatric disorders often emerge. Marijuana is the most common illicit drug abused by youths, typically preceding other illicit substances. We aimed to evaluate the complex and poorly studied relationships between marijuana use, psychiatric symptoms, and cortisol levels in young marijuana users. Psychiatric symptoms and salivary cortisol were measured in 122 youths (13-23years old) with and without marijuana use. Psychiatric symptoms were evaluated using the Symptom-Checklist-90-R and Brief Psychiatric Rating Scale. Mid-day salivary cortisol levels were measured. Additionally, salivary cytokine levels were measured in a subset of participants. Although the cortisol levels and salivary cytokine levels were similar, the young marijuana users had more self-reported and clinician rated psychiatric symptoms than controls, especially anxiety-associated symptoms. Moreover, marijuana users with earlier age of first use had more symptoms, while those with longer abstinence had fewer symptoms. Greater cumulative lifetime marijuana use was also associated with greater psychiatric symptoms. The discordant anxiety (feeling stressed or anxious despite normal cortisol) in the marijuana users, as well as symptom exacerbations with early and continued marijuana use in young marijuana users suggest that marijuana use may contribute to an aberrant relationship between stress response and psychiatric symptoms. The greater symptomatology, especially in those with earlier initiation and greater marijuana usage, emphasize the need to intervene for substance use and perceived anxiety in this population.

Periodontitis and obstructive sleep apnea's bidirectional relationship: a systematic review and meta-analysis.

The aim of this study is to evaluate the association between periodontal disease and obstructive sleep apnea (OSA). Electronic search using PubMed, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Trial Registry, Cochrane Database of Systematic Reviews, Scopus, and Embase was carried out for randomized controlled trials, longitudinal, cohort, case-control, and epidemiological studies on humans, published until October 2014. Manual searches were also performed. The participants considered were adult subjects with OSA and chronic periodontitis. The authors reviewed all articles and extracted data using a customized data abstraction sheet. Methodological quality assessment was carried out using the Newcastle-Ottawa Quality Assessment Scale. Six studies met the inclusion criteria set for this review. They evaluated the association between periodontal disease and OSA and the efficacy of periodontal interventions on OSA occurrence and severity. The periodontal disease outcome measures included clinical attachment loss, periodontal pocket depth, oral hygiene indices, radiographic alveolar bone loss, and salivary cytokines. Meta-analysis of four studies revealed a statistically significant association between periodontal disease and OSA (pooled odds ratio = 1.65, 95% confidence interval (CI) = 1.11, 2.46, P = 0.01). There is insufficient evidence on the efficacy of periodontal disease interventions. There is some evidence to a plausible association between periodontal disease and OSA. Evidence on the efficacy of periodontal disease interventions is insufficient. The causal-effect relationship of periodontal disease and OSA is debatable. Further research with case-control studies is warranted.

Can biomarkers differentiate pain and no pain subgroups of nonverbal children with cerebral palsy? A preliminary investigation based on noninvasive saliva sampling.

Assessing and treating pain in nonverbal children with developmental disabilities are a clinical challenge. Current assessment approaches rely on clinical impression and behavioral rating scales completed by proxy report. Given the growing health relevance of the salivary metabolome, we undertook a translational-oriented feasibility study using proton nuclear magnetic resonance (NMR) spectroscopy and neuropeptide/cytokine/hormone detection to compare a set of salivary biomarkers relevant to nociception. Within-group observational design. Tertiary pediatric rehabilitation hospital. Ten nonverbal pediatric patients with cerebral palsy with and without pain. Unstimulated (passively collected) saliva was collected using oral swabs followed by perchloric acid extraction and analyzed on a Bruker Avance 700 MHz NMR spectrometer. We also measured salivary levels of several cytokines, chemokines, hormones, and neuropeptides. Partial least squares discriminant analysis showed separation of those children with/without pain for a number of different biomarkers. The majority of the salivary metabolite, neuropeptide, cytokine, and hormone levels were higher in children with pain vs no pain. The ease of collection and noninvasive manner in which the samples were collected and analyzed support the possibility of the regular predictive use of this novel biomarker-monitoring method in clinical practice.

Salivary cytokines as a minimally-invasive measure of immune functioning in young children: correlates of individual differences and sensitivity to laboratory stress.

There is growing interest in minimally-invasive measures of environmentally-responsive biological systems in developmental science. Contributing to that endeavor, this study explores the intercorrelations, correlates, and task-sensitivity of proinflammatory salivary cytokines in childhood. Saliva was sampled from 125 healthy five-year old children (49% male) across a series of cognitive and emotional challenge laboratory tasks. Samples were assayed for cytokines (IL-1β, IL-6, IL-8, TNFα), and markers of hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system (ANS) activation (salivary cortisol and alpha-amylase [sAA]). Cytokines were positively intercorrelated and task-sensitivity varied. Except IL-8, cytokines were elevated in children with oral health issues and tobacco smoke exposure. Among boys, cytokines were positively related to sAA and negatively related to cortisol. The findings suggest that in healthy children, salivary cytokine levels reflect compartmentalized oral immune activity. Associations between ANS and HPA activity and cytokines in saliva may present opportunities for minimally-invasive methods to explore neuroendocrine-immune interactions during development.

Effects of the Menstrual Cycle and Acute Aerobic Exercise on Cytokine Levels

Objective: The purposes of this study were: 1) to investigate the effects of menstrual cycle on the basal levels of salivary cytokines (interleukin IL-6 and IL-8) in young healthy women; 2) to examine the influences of prolonged aerobic exercise at ventilatory threshold (VT) on salivary and circulating IL-6 and IL-8 concentrations during menstrual phase. Methods: Eight healthy women participated in three visits (saliva sampling during menstrual, follicular and luteal phases) and two trials (exercise and resting trials during a separate menstrual phase). The exercise trial involved a 60- min cycling at VT and the resting trial involved resting for 90 min.Saliva and blood samples were taken at before, immediately after and 30 min post-exercise and equivalent times during the resting trial. Results: Salivary IL-6 level was higher during the follicular phase than the luteal phase at rest. Salivary IL-8 immediately post-exercise was higher than pre-exercise, and circulating IL-6 was significantly increased from pre-exercise to immediately post-exercise and 30 min post exercise. Conclusion: The results showed that salivary cytokines are influenced by menstrual cycle and prolonged exercise during menstrual phase.However the levels of IL-6 and IL-8 in saliva do not closely reflect those in plasma, and therefore might reflect a local level of inflammation.

Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis.

ObjectivesThe objective of this study was to identify salivary and serum concentrations of interleukin (IL)-8, IL-6, and tumor necrosis factor alpha (TNF-α) in patients with oral lichen planus, oral leukoplakia, oral submucous fibrosis, and healthy controls.Materials and MethodsPatients selected included 54 oral lichen planus (41 to 65 years), 50 oral leukoplakia (42 to 65 years), 51 oral submucous fibrosis (41 to 65 years), and 50 healthy controls (42 to 65 years). Oral lichen planus, oral leukoplakia, and oral submucous fibrosis cases were diagnosed using histopathological analysis. Salivary and serum cytokine concentrations were measured using enzyme-linked immunoassay kits in all subjects.ResultsThe levels of serum and salivary TNF-α, IL-6, and IL-8 were statistically significantly increased in oral leukoplakia, submucous fibrosis, and lichen planus in contrast to normal healthy subjects (P<0.05). Serum and salivary correlation analysis revealed strong and highly significant correlations for TNF-α, IL-6, and IL-8 in all groups (r=0.72-0.82, P<0.05).ConclusionSalivary and serum cytokines were also elevated when analyzed in oral precancerous lesions. Thus, salivary and serum IL-8, IL-6, and TNF-α levels might act as diagnostic markers for detection of oral precancer.

Comparing methods to collect saliva from children to analyze cytokines related to allergic inflammation

Comparing methods to collect saliva from children to analyze cytokines related to allergic inflammation

Salivary inflammatory cytokines may be novel markers of carotid atherosclerosis in a Japanese general population: The Suita study

ObjectiveSalivary biomarkers have been recently useful of periodontal disease, which is also risk factor of atherosclerosis. However, there are few studies of the association between salivary inflammatory cytokines and carotid atherosclerosis. We aimed to clarify the association between salivary inflammatory cytokines and periodontal disease and carotid atherosclerosis in a general urban population. MethodsWe studied 608 Japanese men and women (mean age: 65.4 years) in the Suita study. Carotid atherosclerosis was evaluated by high-resolution ultrasonography with atherosclerotic indexes of intima-media thickness (IMT). Periodontal status was evaluated by the Community Periodontal Index (CPI). Salivary levels of interleukin-1β, interleukin-6, tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) were measured by enzyme linked immunosorbent assay. The risks of carotid atherosclerosis (≥75th percentiles of mean- [0.88 mm] and Max-IMT [1.50 mm]) according to the quartiles of salivary inflammatory cytokines were compared using of adjusted-logistic regression models. Results and conclusionAll salivary inflammatory cytokines were positively associated with CPI. The adjusted odds ratios for carotid atherosclerosis of mean-IMT in the highest quartile of interleukin-6 and TNF-α were higher than those in the lowest quartiles (OR = 2.32 and 2.88; 95% confidence intervals = 1.19–4.51 and 1.51–5.49, respectively). The adjusted odds ratio for carotid atherosclerosis of mean-IMT in the highest quartile of PGE2 was greater than those in the lowest quartile in women (OR = 2.78; 95% confidence intervals = 1.11–6.95). In conclusion, higher levels of salivary inflammatory cytokines were associated with both periodontal disease and carotid atherosclerosis. Selected salivary inflammatory cytokines may be useful screening markers for periodontal disease and carotid atherosclerosis.

Prospective evaluation of cytokine in saliva of preterm and fullterm neonates

Little is known about the ontogeny of the cytokines in saliva of newborn. Previous studies showed that levels of immunoglobulin A (IgA) in saliva could be influenced by prematurity. So, the aim of this study was to analyze the levels of interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and interferon gamma (IFN-γ) in sample saliva of fullterm (FT) and preterm (PT) neonates at birth (T0) and after 3 months of age (T3). Saliva from 50 infants (25 FT and 25 PT) were collected at T0 and T3 and analyzed by Luminex Corporation (Austin, Texas, United States) multiplex assay. Clinical characteristics and social–economic data were assessed through questionnaires. All cytokines could be detected at birth in levels higher than found in T3. The mean levels and frequency of detection of cytokines were significantly higher in PT than FT at T0 (P<0.05). There were a positive association between IL-10 and infection (P<0.05) and IL-6 and stress (P<0.005). Salivary cytokines were detected within the first hours after birth and their levels decreased after 3 months. The cytokine levels were different between PT and FT children and appear to be influenced by stress situation and/or antigenic microbial challenge. The results confirm the necessity for further studies about the mucosal immune system by using of saliva as a source of diagnostic by identification of biomarkers of the status of the immune.

Salivary Cytokines and the Association Between Obstructive Sleep Apnea Syndrome and Periodontal Disease

A higher prevalence of periodontal disease has been reported in patients with obstructive sleep apnea syndrome (OSAS), and these two chronic conditions may be linked via inflammatory pathways. The aim of the present study is to evaluate the salivary interleukin (IL)-1β, IL-6, IL-21, IL-33, and pentraxin-3 (PTX3) concentrations in patients with and without OSAS. A total of 52 patients were included in the study. Thirteen individuals were in the control (non-OSAS) group, 17 were in the mild/moderate OSAS group, and 22 were in the severe OSAS group. Clinical periodontal measurements were recorded, and saliva samples were obtained before initiation of periodontal intervention. Enzyme-linked immunosorbent assay was used to determine salivary cytokine concentrations. Data were statistically analyzed using D'Agostino-Pearson omnibus normality, Spearman ρ rank, Kruskal-Wallis, and Dunn tests. Salivary IL-6 and IL-33 concentrations were similar in the two OSAS groups (P >0.05), which were statistically higher than the control group (P <0.05). IL-1β, IL-21, and PTX3 concentrations were similar in the study groups. The only significant correlation between clinical periodontal parameters and salivary cytokines was found between clinical attachment level (CAL) and IL-21 (P = 0.02). Highly significant correlations were found between probing depth, CAL measures, and indicators of OSAS severity (P <0.01). The present findings suggest that OSAS may have an increasing effect on salivary IL-6 and IL-33 concentrations regardless of OSAS severity. Additional investigation is required to elucidate a potential bidirectional relationship between OSAS and periodontal disease.

Mo1679 Development and Validation of a Novel Ultra-Mobile Ambulatory Total Parenteral Nutrition Model

G A A b st ra ct s previously have described the presence of cytokines in saliva which also are present in blood and esophageal tissue and have been suggested as playing a fundamental role in the pathogenesis of EoE. However, the usefulness of these salivary cytokines in discriminating between patients with/without EoE and their potential correlation with esophageal eosinophilia have not been examined. Methods In this cross−sectional study, we collected saliva using oral swabs (OS; Salimetrics Oral Swab®, Salimetrics LLC, PA) at the time of upper gastrointestinal endoscopy in sixteen children being evaluated for gastroesophageal and/or dyspeptic symptoms. Children with oral lesions, neurodevelopmental disorders, inflammatory bowel disease, or celiac disease were excluded. Six children were diagnosed with EoE and ten children had no evidence of EoE and were considered Controls (Table). Esophageal histology was compared between groups. Salivary cytokines: IL−4, IL−5, and IL−13 were measured on a high sensitivity human multiplex platform, and eotaxin 3 (Eo3) and thymic stromal lymphopoietin (TSLP) by sandwich ELISA technique. Differences between groups were evaluated using the Wilcoxon rank sum test. Spearman's correlation was performed to examine potential associations between salivary cytokines and esophageal eosinophils per high powered field (eos/hpf). Results See Table. Age and sex were comparable between groups. Median salivary IL−5 and IL−4 concentrations were significantly greater in patients with EoE than in Controls. In contrast, there were no differences between groups in median IL−13, Eo3, or TSLP concentrations although values were numerically higher in patients with EoE. Salivary IL−4 and IL−5 were positively correlated with eos/hpf in the distal esophagus (Spearman's ρ=0.53; P=0.03 and ρ=0.56; P=0.02, respectively). In contrast, IL−13, Eo3, and TSLP did not correlate with histologic findings. Conclusions Our preliminary data suggest that salivary cytokines, specifically IL−4 and IL−5 have the potential to distinguish children with vs without EoE. Salivary concentrations of these cytokines appear to reflect esophageal eosinophilic infiltration in EoE. Confirmation of our findings in a larger sample with additional types of disease controls may simplify management and reduce the cost of caring for children with EoE. Table: Summary of results

OI0334 Salivary cytokine profile in oral chronic graft-vs-host disease and common oral conditions

OI0334 Salivary cytokine profile in oral chronic graft-vs-host disease and common oral conditions

The Role of Salivary Cytokines in Patients with Oral Lichen Planus

The Role of Salivary Cytokines in Patients with Oral Lichen Planus

Cytokine Alteration In Multiple Myeloma (MM) Patients and Bisphosphonate (BP)-Related Osteonecrosis Of The Jaw (BRONJ)

IntroductionBRONJ is a complex process that involves interplay of drug effect, bacteria-host immune interactions, and alteration of cytokines and inflammatory mediators leading to impaired healing of the mucosa. In this prospective study, we evaluated MM patients on long term BP therapy to define risk factors and explore cytokine changes in relationship to BP infusion and development of BRONJ. Methods and patients110 MM patients were enrolled on the study and followed for 18 months. Patients were receiving zoledronic acid infusions once a month (n=75) or every 3 months (n=35) for those in stable remission > 3 years. Patients had clinical and oral evaluations at each visit. Blood samples were collected at baseline and every 6 months. Saliva samples were obtained every 3 months (before and 15 minutes after zoledronic acid infusions). Cytokine expression was analyzed using MULLIPLEX MAP Multiplex Assay (EMD Millipore, MA). ResultsMedian time from MM diagnosis was 3.7 years (range: 2.5-13) for 100 patients; 10 newly diagnosed patients had a median of 7 months (range: 1-9). Median age was 57 years (range: 33-81); 58 were Caucasians, 49 African American, 3 Asians; 68 were males. At study entry, 87 (79%) patients were in remission: CR (n=35, 32%) of them 15 were in CR for > 7 years, PR (n=52, 47%) and PD (n=23, 21%). At study entry, 24 patients were not receiving any MM therapy; most were on maintenance with lenalidomide (n=59), and 10 were receiving induction. While on study, 50 patients progressed and received salvage therapies that included: bortezomib based (n=14), lenalidomide (n=6), carfilzomib (n=16) and other clinical trials (n=14). Thirteen patients died: 9 from complications of relapsed MM and 4 from other causes. Eighteen patients withdrew consent for sample collection and dental evaluations but were followed clinically. Most patients had history of dental procedures (extractions, n=80). The predominant pathology detected during dental evaluations included: moderate/severe periodontal disease (n=45) and gross dental caries (n=15); while on the study, 66 patients continued regular dental cleaning and 10 had dental extractions. During the 18 months of follow up, 14 patients developed new lesions with exposed bone for 8 weeks, meeting the definition of BRONJ. Median time from MM diagnosis to BRONJ was 5.7 years (the 95% CI: 1.9-12.0). BRONJ patients were in remission (n=9), receiving monthly zoledronic acid (n=9), dental extractions (n=9) and three had recurrent BRONJ. There was no association found between BRONJ and diabetes, smoking, or dental pathology. BRONJ treatment was conservative consisting of antibiotics and holding BP therapy. There are 5 patients who continue to have non-healing BRONJ lesions.Saliva and serum samples obtained during this study (baseline, midpoint (6-9 months), end (12-18 months) were assessed for the following cytokines: interleukins (IL)-1β, -6, and -17; TNF-α, IFN-α, TGF-β, MIP-1 α β, MMP-9, Osteopontin, Osteocalcin, RANKL, Osteoprotregerin, VEGF and EGF in 43 patients with ONJ (n=13) and without ONJ (n=30). There were statistically significant lower levels of VEGF and TGF- β (p= .04 and .02, respectively) in the serum overtime in patients who developed BRONJ, figure below. In the saliva cytokines levels were significantly lower in patients who developed BRONJ vs no BRONJ at baseline, before and after zoledronic acid infusions: [Mean pg/ml (SD), p value]: MIP-1 β [14 (3) vs 6(2), p=0.01]; IL-1 β [1824 (1518) vs 72 (38), p=0.04]; IL-6 [15 (4) vs 3 (3), p=0.02]; TNF-α [10 (3) vs 3 (2), p=0.09]. Osteoprotregerin [213 (39) vs 125 (26), p=0.07] was borderline higher in those without BRONJ. [Display omitted] Conclusionthe incidence of BRONJ remains high at 12% after a median of 5 years of BP use. Dental extraction remains the most significant risk factor for BRONJ. The salivary cytokine repertoire suggests M1 macrophage polarization (recently reported by Zhang et, Clin Cancer Res 2013), in response to injury. The low levels of VEGF and TGF in the serum in response to injury further impair the mucosal healing. Time points1. Baseline, 2. Midpoint (6-9 months), 3. End of study (12-18 months) Disclosures:No relevant conflicts of interest to declare.