Clinical practice guidelines for oral management of Sjögren disease: Dental caries prevention

"BACKGROUND: Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. RESULTS: Final recommendations for patients with Sjögren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The incidence of caries in patients with Sjögren disease can be reduced with the use of topical fluoride and other preventive strategies."

Pain in primary Sjögren's syndrome: the role of catastrophizing and negative illness perceptions.

OBJECTIVES: Pain is a major factor in health quality in Sjögren's syndrome (SS), but little is known about the factors that contribute to pain severity. Because pain perception has been linked to catastrophizing in other diseases, we assessed subjects with primary SS (pSS) to explore a possible link between pain, illness appraisal, and catastrophizing. METHOD: A total of 92 subjects who met American-European consensus criteria for the diagnosis of pSS completed a questionnaire that included health history, medication use, illness perceptions, pain severity, mood, fatigue, pain anxiety, and pain catastrophizing. Linear regression was used to test the effect of each variable on pain severity. Multivariate models were constructed using backwards elimination to assess the significant predictors of pain severity. RESULTS: From linear regression analysis, catastrophizing was more strongly predictive of pain severity than age, fatigue, depression, or anxiety in both seropositive and seronegative pSS patients. In the multivariate model identified using backwards selection, four variables (pain catastrophizing, fibromyalgia status, serological status, and the conviction that illness would have severe consequences) predicted 55% of the variance in pain severity. CONCLUSIONS: Pain catastrophizing was a significant predictor of pain severity in both seropositive and seronegative pSS patients. This study suggests that behavioural interventions designed to reduce pain catastrophizing and negative appraisal of illness could be of benefit in pSS patients. Research is needed to test the effect of psycho-educational therapies on key patient-reported outcomes, particularly pain, depression, and fatigue, in pSS.

A comparison of screening methods in two early phase oral leukoplakia clinical trials.

OBJECTIVES/INTRODUCTION: Clinical trial accrual for oral dysplasia is difficult in the United States and elsewhere. Patients with dysplastic oral leukoplakia progress to frank invasive carcinoma at a rate of 5-37% over 5 years. We compared two clinical trial screening efforts to hopefully devise better accrual strategies to these types of clinical trials. METHODS: For the first trial, we identified 244 patients with dysplastic oral leukoplakia in our university database and a media campaign. Patients were notified and screened by examination and biopsy. For the second clinical trial, we established a preneoplastic lesions clinic and teaching and communications network with regional oral healthcare professionals. RESULTS: Only one of 244 patients accrued to the first clinical trial through an organized screening effort based on database/medical records review. The second clinical trial accrued 16/30 screened patients through redirected efforts in teaching, communications, and a preneoplastic lesions clinic. CONCLUSION: We conclude that significant difficulties resulted from medical record/database review of leukoplakia patients as a screening method for leukoplakia clinical trial entry. We feel that persistent direct contact and education of healthcare professionals who are likely to examine leukoplakia patients improved accrual to the second clinical trial.

Primary Sjogren's syndrome: cognitive symptoms, mood, and cognitive performance.

OBJECTIVE: To investigate the relationships between self-reported cognitive abilities, psychological symptoms and neuropsychological outcomes in PSS. METHODS: Patients with Primary Sjogren's syndrome (PSS) and healthy controls completed a comprehensive neuropsychometric battery and questionnaires: the Centers for Epidemiological Scale-Depression, the Profile of Fatigue-mental domain (Prof-M) for cognitive symptoms, Fatigue Severity Scale, and the Short-Form McGill Pain Questionnaire. RESULTS: Female patients with PSS (N = 39) were similar to controls (N = 17) in estimated premorbid intellectual function, age and education. Depression (P = 0.002), cognitive symptoms (P = 0.001), fatigue (P = 0.000003), and pain (P = 0.024) scores were greater in the patient group. Patients with PSS demonstrated inferior performance relative to controls in psychomotor processing (P = 0.027) and verbal reasoning (P = 0.007). Patients with PSS with and without depression had similar performance on multiple tests, but depressed patients had significantly lower scores for executive function (P = 0.041). Cognitive symptoms correlated with verbal memory (P = 0.048), whereas pain correlated with executive function measures (Stroop, P = 0.017) and working memory (Trails B, P = 0.036). In the regression model, depression and verbal memory were independent predictors that accounted for 61% of the variance in cognitive symptoms. CONCLUSION: The Prof-M is a simple self-report measure which could be useful in screening PSS subjects who may benefit from detailed psychometric evaluation. Our results are consistent with the hypothesis that depression and verbal memory impairment are overlapping but independent aspects of neural involvement in PSS. While pain and depression are significant confounders of cognitive function in PSS, this study suggests that impaired verbal reasoning ability in PSS is not attributable to pain or depression.

A metaproteomic analysis of the human salivary microbiota by three-dimensional peptide fractionation and tandem mass spectrometry.

Metagenomics uses gene expression patterns to understand the taxonomy and metabolic activities of microbial communities. Metaproteomics applies the same approach to community proteomes. Previously, we used a novel three-dimensional peptide separation method to identify over 2000 salivary proteins. This study used those data to carry out the first metaproteomic analysis of the human salivary microbiota. The metagenomic software MEGAN generated a phylogenetic tree, which was checked against the Human Oral Microbiome Database (HOMD). Pathway analyses were performed with the Clusters of Orthologous Groups and MetaCyc databases. Thirty-seven per cent of the peptides were identifiable only at the level of cellular organisms or bacteria. The rest were distributed among five bacterial phyla (61%), archea (0.5%), and viruses (0.8%); 29% were assignable at the genus level, and most belonged to Streptococcus (17%). Eleven per cent of all peptides could be assigned to species. Most taxa were represented in HOMD and they included well-known species such as periodontal pathogens. However, there also were 'exotic' species including aphid endosymbionts; plant, water, and soil bacteria; extremophiles; and archea. The pathway analysis indicated that peptides were linked to translation (37%), followed by glycolysis (19%), amino acid metabolism (8%), and energy production (8%). The taxonomic structure of the salivary metaproteome is very diverse but is dominated by streptococci. 'Exotic' species may actually represent close relatives that have not yet been sequenced. Salivary microbes appear to be actively engaged in protein synthesis, and the pathway analysis is consistent with the metabolism of salivary glycoproteins.

FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity.

OBJECTIVE: The aim of this study was to determine the correlation between the number of FOXP3(+) T cell in lesions and the disease activity of patients with oral lichen planus (OLP). MATERIALS AND METHODS: The expression of FOXP3 was investigated using immunohistochemical staining and real-time RT-PCR in 23 OLP lesions and 12 controls. Changes of FOXP3(+) Treg in peripheral blood from three patients' pre and post-treatment were assessed using flow cytometry. RESULTS: Few FOXP3(+) cells were detected in controls, but an increased number of FOXP3(+) cells were observed in lesions (n = 20, 40.99 +/- 24.68 cells per high-power field - hpf). Furthermore, the frequency of FOXP3(+) Treg in reticular OLP (n = 7, 63.6 +/- 23.2 cells per hpf) was significantly higher than that in erythematous/erosive OLP (n = 13, 28.8 +/- 16.8 cells per hpf, P = 0.001). In addition, negative correlation was found between the number of FOXP3(+) Treg and disease activity (correlation oefficient = -0.557, P = 0.013). The proportion of FOXP3(+) Treg showed remarkable increase in peripheral blood from patients after treatment (1.39 +/- 0.71%vs 4.91 +/- 1.59%). CONCLUSIONS: These data indicated that FOXP3(+) Treg were involved in the pathogenesis of OLP and correlated with disease's subtype and activity.

Peripheral blood gene expression profiling in Sjögren's syndrome.

Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. The affected cases commonly present with oral and ocular dryness, which is thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in the peripheral blood. We first analyzed 21 SS cases and 23 controls, and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent data set of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B- and T-cell receptor, insulin-like growth factor-1, granulocyte macrophage-colony stimulating factor, peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease showed that expression levels for most interferon-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting interferon-signaling pathway may prove most effective in the subset of SS cases that produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS, and provide numerous candidate disease markers for further study.

Methamphetamine abuse and dentistry.

Methamphetamine is a highly addictive powerful stimulant that increases wakefulness and physical activity and produces other effects including cardiac dysrhythmias, hypertension, hallucinations, and violent behavior. The prevalence of methamphetamine use is estimated at 35 million people worldwide and 10.4 million people in the United States. In the United States, the prevalence of methamphetamine use is beginning to decline but methamphetamine trafficking and use are still significant problems. Dental patients who abuse methamphetamine can present with poor oral hygiene, xerostomia, rampant caries ('Meth mouth'), and excessive tooth wear. Dental management of methamphetamine users requires obtaining a thorough medical history and performing a careful oral examination. The most important factor in treating the oral effects of methamphetamine is for the patient to stop using the drug. Continued abuse will make it difficult to increase salivary flow and hinder the patient's ability to improve nutrition and oral hygiene. Local anesthetics with vasoconstrictors should be used with care in patients taking methamphetamine because they may result in cardiac dysrhythmias, myocardial infarction, and cerebrovascular accidents. Thus, dental management of patients who use methamphetamine can be challenging. Dentists need to be aware of the clinical presentation and medical risks presented by these patients.

Microarrays: applications in dental research.

Revolutionary advances are underway that will dramatically change our understanding of oral diseases. The phenomenal progress being made in biomedical research is in large part fueled by advances in our overall knowledge of the human genome, development of microarray technology that allows comprehensive and unbiased evaluation of global biologic pathways and networks, and expanded computational abilities. Expectations are that nearly all clinical areas in dentistry and oral medicine will be affected by advances in molecular medicine, which in turn, promises to lead to more accurate diagnosis, effective disease monitoring, and development of targeted and specific therapies. This review provides a brief overview of microarray technologies and highlights several key examples from research efforts in dentistry and oral medicine using these powerful new tools.

Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone.

OBJECTIVE: To explore the potential of detecting the level of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha (IL-1-alpha), IL-6, and IL-8 in whole unstimulated saliva (WUS) in monitoring the therapeutic effects of topical dexamethasone on these salivary cytokines in subjects with erosive oral lichen planus (OLP). STUDY DESIGN: Thirteen definitively diagnosed OLP subjects were enrolled in the study as were 13 age- and sex-matched controls. The OLP subjects were treated with 0.1% dexamethasone oral rinse for 6 weeks. Prior to treatment and at the end of clinical trial, the visual analog scale (VAS) for symptoms was recorded, WUS was collected and these proinflammatory cytokines were analyzed by ELISA. RESULTS: Following the dexamethasone treatment, the levels of TNF-alpha, IL-1-alpha, IL-6, and IL-8 were decreased significantly, and IL-1-alpha and IL-8 were detected at a level without a statistically significant difference from controls. VAS value was decreased significantly and was found to significantly correlate with the decrease in IL-1-alpha and IL-8 levels. CONCLUSIONS: These preliminary results indicate that salivary analysis of NF-kappaB-dependent cytokines may be applied to monitoring the therapeutic response of OLP.

Blood pressure outcomes of dental patients screened chronobiologically: a seven-year follow-up.

BACKGROUND: This article is a follow-up on a 1998 article in JADA. The blood pressure, or BP, of 23 of 24 normotensive patients was monitored at 15-minute intervals for a total of nine days, in three consecutive sessions of four, two and three days, respectively, separated by a few weeks. METHODS: Twelve patients were reached by phone seven years after the prior chronobiologically interpreted monitoring to ascertain their cardiovascular status since the initial monitoring. RESULTS: Only two of the 12 patients reached in follow-up had abnormalities in all three sessions, and only these two patients reported having experienced an adverse vascular event (one a myocardial infarction, the other coronary artery bypass graft surgery). The difference in outcome between the patients with chronobiological abnormality in all three sessions vs. the pool of those with abnormality in only two, one or none of the sessions is statistically significant. CONCLUSIONS: Even a five-day (and sometimes a longer) profile, while greatly preferred to single measurements, may not suffice for a definitive diagnosis of certain patients. Retrospectively, the 864 measurements, on the average, on each person in our study could have served for a recommendation to each person. Chronobiologically interpreted BP and heart rate monitoring for a week or longer as a start detects high-risk states that may be missed by conventional casual measurements that are rarely accompanied by one-day profiles. CLINICAL IMPLICATIONS: The dentist has an important opportunity for conveying the importance of monitoring BP and heart rate for a week to detect an abnormal variability, and for implementing this monitoring. Dentists can educate patients regarding the need for screening and for interpreting the results for variability, and contribute to their overall health by referring them to their physicians when treatment is indicated.

About 8- and approximately 84-h rhythms in endotheliocytes as in endothelin-1 and effect of trauma.

Population densities (PD) of capillaries (C) and endotheliocytes (E) were determined in pinnal dermis of C57BL mice before and after trauma. Moving (and overall) least-squares spectra before trauma detected in EPD (versus CPD) pronounced 3.5-day (circasemiseptan) and 8-h oscillations corresponding to components of the endothelin-1 chronome in human blood plasma reported earlier. Circadians were more pronounced in CPD. After trauma, circasemiseptan oscillations appeared also in CPD; their period gradually shortened and in two weeks split into about 2.5- and about 4.5-day oscillations; and circadian components became very pronounced. The pre-traumatic chronome was not restored within three weeks following trauma.

Clinical evaluation of a commercially available oral moisturizer in relieving signs and symptoms of xerostomia in postirradiation head and neck cancer patients and patients with Sjögren's syndrome.

A major complication of irradiation therapy for head and neck cancer is salivary gland dysfunction and xerostomia. The purpose of this clinical investigation was to evaluate the effects of a commercially available oral moisturizer (Optimoist) on salivary flow rate, symptoms of xerostomia, oral pH, oral microflora, and swallowing in postirradiation head and neck cancer patients (XRT) and patients with Sjögren's syndrome (SS). Subjects who were post-XRT and subjects with SS (n = 24; mean age = 54.1) discontinued their use of any salivary substitute or moisturizer for 2 weeks prior to entering the study. Baseline whole unstimulated saliva was collected for 5 minutes using a standard sialometric technique. Candida albicans and Lactobacillus cultures were performed using kits from Orion Diagnostica, Inc., and a pH analysis was performed on the salivary sample using a Markson (model 00663) pH meter. Swallowing was assessed by clinical measures by videofluoroscopic techniques. Several subjective assessments were performed to evaluate symptoms of xerostomia. Subjects were instructed in the use of a daily diary and to use only the provided article ad libitum for a period of 2 weeks. After the 2-week period, the results indicated significant subjective and objective improvements in signs and symptoms of xerostomia. Whole unstimulated salivary flow rate improved from (mean +/- SEM) 0.1150 +/- 0.02 to 0.2373 +/- 0.09 mL/min. Salivary pH did not change. Global subjective improvement in xerostomia improved in 58% of the subjects. Candida colonization decreased in 43% of the subjects. There was no change in Lactobacilli colonization. Swallowing objectively improved in 75% of subjects. These results indicate significant improvement in both signs of hyposalivation and symptoms of xerostomia with the use of Optimoist in postirradiation head and neck cancer patients and patients with SS.

An update on the management for the dental patient with Sjögren's syndrome and xerostomia.

Sjögren's syndrome is a chronic and uncomfortable inflammatory condition for the individuals who suffer from it. There are many and varied systemic and oral complications associated with Sjögren's syndrome. It is also a complex and challenging condition for the dentist to diagnose and manage. The key concepts are early recognition and intervention to prevent the secondary complications from hyposalivation. To the degree possible, salivary flow should be restored by either artificial salivas or stimulated by secretogogues or both, which is usually the case. Atrophy and secondary infections of the oral mucosa should be properly identified, effectively treated, and frequently monitored. Pilocarpine HCl (Salagen) has been shown to be effective in increasing salivary flow in patients with SS. Preventive and supportive therapy including supplemental fluorides, dietary assessment, and frequent professional recalls are imperative to maintaining the oral health of the patient with SS.

Sjögren's syndrome.

Sjögren's syndrome (SS) is a progressive autoimmune rheumatic disorder. Its precise etiology is unknown, although several contributing factors have been identified. One theory is that the condition results from complications related to infection with the Epstein-Barr virus. Primary exposure to or reactivation of Epstein-Barr virus elicits expression of the human leukocyte antigen complex. This is recognized by T lymphocytes (CD 4+) resulting in the release of cytokines (tumor necrosis factor, interleukin-2, interferon-gamma, and others). A genetic marker specific for Sjögren's syndrome, HLA-DR4, has been identified. According to the World Health Organization, the prevalence of Sjögren's syndrome is unknown. A recent epidemiologic study in Sweden estimated the prevalence in the adult population to be 2.7%. In the United States, 10 years ago, the number of patients with Sjögren's syndrome was thought to be fewer than 100,000. This number today is estimated to be more than 1 million. Sjögren's syndrome has been reported in nearly every major country of the world, and the geographic distribution of cases appears to be relatively uniform. Sjögren's syndrome typically affects women (90%) during the fourth or fifth decade of life. Isolated cases of Sjögren's syndrome in children have been reported.

A comparison of three methods for detecting Candida albicans in patients with Sjögren's syndrome.

OBJECTIVE: An immediate chairside technique (Latex Candida) for the detection of Candida albicans was compared with a simple tube culturing technique (Oricult) and the traditional laboratory culturing technique in patients with Sjögren's syndrome. METHOD AND MATERIALS: Subjects with primary (n = 9) and secondary (n = 9) Sjögren's syndrome (mean age of 56.7 years; all female) and an age- and sex-matched group of control subjects (n = 9) were selected. Three different methods for culturing Candida albicans were performed for each subject. One culturette was plated on a trypticase soy-agar streptomycin-vancomycin medium plate and incubated for 48 hours at 37 degrees C. Another swab was plated on a reagent paper with the Latex Candida test kit. The third swab was placed in a culture media tube using the Oricult kit and incubated for 48 hours at 37 degrees C. RESULTS: All three techniques indicated a significant difference in the prevalence of Candida between the control group and both Sjögren's groups. The Latex Candida technique indicated that 78% of all Sjögren's subjects were positive for Candida, while the other two tests indicated that 83% were positive. CONCLUSION: The Latex Candida technique was comparable to Oricult and streptomycin-vancomycin culturing techniques for negative results and was correctly positive for 90% of cases.

An evaluation of a chemical cautery agent and an anti-inflammatory ointment for the treatment of recurrent aphthous stomatitis: a pilot study.

OBJECTIVE: Recurrent aphthous stomatitis is a very common condition, currently treated with anti-inflammatory agents, which palliate the symptoms. The purpose of this clinical trial was to compare a medication commonly used to treat recurrent aphthous stomatitis, Kenalog-in-Orabase, and a newer agent, Debacterol. METHOD AND MATERIALS: Sixty patients diagnosed with recurrent aphthous stomatitis were enrolled in the study. Twenty patients were assigned to each of the two treatment groups, and 20 age- and sex-matched patients were assigned to the control group, which received no treatment. After the diagnosis was made, clinical examinations and ulcer measurements were performed, and a subjective evaluation of symptoms (100-mm visual analog scale) was completed by each subject. The subjects did not use any other medications. Both agents were applied topically (the frequency varied depending on the group of subjects) at specified intervals. Ulcer measurements and subjective evaluations were made at days 0, 3, 6, and 10 for all subjects. RESULTS: In both treatment groups, by day 10, 100% of the ulcers had clinically healed and were no longer causing pain. Patients in the Debacterol group reported a significantly greater decrease in pain at 3 days (> 70%) than did subjects in the other groups (< 20%), although the size of the ulcer did not differ significantly in any of the groups. After day 6, 80% of the ulcers in the Debacterol group had clinically disappeared and no longer caused symptoms, as compared to about 30% in the other groups. CONCLUSION: Patients subjectively reported significantly greater relief from symptoms with Debacterol than with Kenalog-in-Orabase or no treatment. The relief of symptoms associated with recurrent aphthous stomatitis may or may not correspond to clinical improvement, and these two topical medications may affect signs and symptoms of the lesions differently.

s-IgA and cytokine levels in whole saliva of Sjögren's syndrome patients before and after oral pilocarpine hydrochloride administration: a pilot study.

Previous investigations have found elevated levels of s-IgA in the parotid saliva and normal levels in submandibular saliva of patients with Sjögren's syndrome (SS). Fox et al. also found elevated levels of cytokines (i.e., IL-2 and IL-6) in serum, salivary epithelial cells and parotid saliva of patients with SS. The oral administration of pilocarpine hydrochloride stimulates whole and parotid salivary flow. The purpose of this study was to determine the levels of s-IgA and IL-2 and IL-6 in whole saliva before and after administration of pilocarpine hydrochloride in SS subjects. Ten definitively diagnosed SS subjects were enrolled in the study, as were ten controls (C). The mean age was 57.2 years and all subjects were female. Whole unstimulated saliva (WUS) was collected by standard techniques for 5 min, after which the volume and flow rate were determined (mean WUS: SS = 0.047 vs C = 0.480 ml/min). Samples were centrifuged and the immunoglobulin analysis performed on the supernatants by immunoreactivity in a double-sandwich technique as previously described by Rudney et al. Cytokine analysis was performed similarly utilizing commercially available kits from R&D Systems. The results as analyzed by pairwise t-tests revealed comparable levels of s-IgA in the saliva of the SS patients, as compared to controls at baseline (means +/- SEM: SS-IgA = 348.1 +/- 82.0 vs C-IgA = 284.0 +/- 65.1 micrograms/ml; NS). Whole salivary flow was significantly increased (328%) in the SS subject group 60 min after the administration of 5 mg pilocarpine hydrochloride (means +/- SEM: 0.0472 +/- 0.017 vs 0.1546 +/- 0.054 ml/min; P < 0.01). There was no significant change in the concentration of s-IgA in the SS subject group following the pilocarpine dose (means +/- SEM: SS-IgA = 439.9 +/- 121.2 microliters/ml; P = NS). There were elevated levels of IL-2 in the saliva of four out of the ten and IL-6 in two out of the ten SS patients, as compared to controls (means +/- SEM: SS-IL-2 = 127.8 +/- 11.4 vs C-IL-2 = 30.8 +/- 1.6 pg/ml and SS-IL-6 = 41.4 +/- 7.1 vs C-11.6 +/- 2.8 pg/ml). There was also a significant decrease in the concentration of IL-2 in the same four out of ten SS subjects following the pilocarpine dose (means +/- SEM: SS-IL-2 = 32.4 +/- 10.3; P < 0.01). These preliminary results indicate that s-IgA levels do not change with increased salivary flow following the administration of pilocarpine hydrochloride in patients with Sjögren's syndrome. While cytokines are elevated in the whole saliva of some SS patients, a decrease in IL-2 concentration may occur with increased salivary flow.