Cytokine levels and their role in the etiopathogenesis of Burning Mouth Syndrome: A systematic review.

INTRODUCTION: Burning Mouth Syndrome is characterized by variable symptoms that include pain, burning and paraguesia in an otherwise healthy-appearing oral mucosa. Although the etiopathogenesis of Burning Mouth Syndrome is unknown, some studies provide evidence of subclinical inflammation leading to disrupted cytokine levels. AIM: To investigate the expression of cytokines and role in the etiopathogenesis of Burning Mouth Syndrome. METHODS: Online databases (MEDLINE and EMBASE) were searched from November 1986 to November 2018 for case control/cross-sectional studies comparing the levels of cytokines in patients with Burning Mouth Syndrome and healthy controls. RESULTS: A total of eight studies were included in the current review. Four studies were of high and four studies were of moderate quality. Seven studies evaluated IL-6, out of which four showed comparable results, two showed higher levels and one study reported lower levels in Burning Mouth Syndrome patients compared to controls. Four studies assessed IL-2, out of which two reported comparable results whereas one study reported higher levels and one study reported lower levels in Burning Mouth Syndrome patients compared to controls. IL-10 levels were measured in three studies that reported no significant differences in the levels between Burning Mouth Syndrome and healthy controls. DISCUSSION AND CONCLUSION: The etiopathogenesis of Burning Mouth Syndrome is multifactorial. Studies have provided scientific evidence that inflammation plays a key role in Burning Mouth Syndrome pathogenesis. However, whether up-regulation or down-regulation of specific cytokines contribute to the etiopathogenesis of Burning Mouth Syndrome remains debatable. Further high-quality studies with larger sample size and assessing a wider array of cytokines are warranted in order to obtain strong conclusions.

Effect of antidepressant treatment on plasma levels of neuroinflammation-associated molecules in patients with somatic symptom disorder with predominant pain around the orofacial region.

OBJECTIVE: Burning mouth syndrome (BMS) and atypical odontalgia (AO) are examples of somatic symptom disorders with predominant pain around the orofacial region. Neuroinflammation is thought to play a role in the mechanisms, but few studies have been conducted. We aimed to better understand the role of neuroinflammation in the pathophysiology and treatment of BMS/AO. METHODS: Plasma levels of 28 neuroinflammation-related molecules were determined in 44 controls and 48 BMS/AO patients both pretreatment and 12-week post-treatment with duloxetine. RESULTS: Baseline plasma levels of interleukin (IL)-1ß (p < .0001), IL-1 receptor antagonist (p < .001), IL-6 (p < .0001), macrophage inflammatory protein-1ß (p < .0001), and platelet-derived growth factor-bb (.04) were significantly higher in patients than in controls. Plasma levels of granulocyte macrophage colony stimulating factor were significantly higher in patients than in controls (p < .001) and decreased with treatment (.009). Plasma levels of eotaxin, monocyte chemoattractant protein-1, and vascular endothelial growth factor decreased significantly with treatment (p < .001, .022, and .029, respectively). CONCLUSIONS: Inflammatory mechanisms may be involved in the pathophysiology and/or treatment response of somatic symptom disorders with predominant pain around the orofacial region.

Neuropeptides in saliva of subjects with burning mouth syndrome: a pilot study.

OBJECTIVE: A neuropathic basis has been suggested for burning mouth syndrome (BMS) and an altered concentration of neuropeptides has been reported in lingual oral mucosa and saliva in this disease. The aims of this study were to compare the levels of nerve growth factor (NGF), substance P (SP) and degranulation products from mast cells and neutrophils in the saliva of BMS subjects with those of control subjects. MATERIAL AND METHODS: Salivary flow rate, protein concentration, NGF peptide and mRNA, SP, mast cells tryptase, neutrophil myeloperoxidase and calprotectin were analyzed in saliva of 20 BMS subjects and of 20 age- and gender-matched healthy subjects. RESULTS AND CONCLUSIONS: NGF peptide and tryptase activity were shown to be significantly and persistently higher in saliva of BMS subjects, with respect to control values. Conversely the salivary levels of SP were shown to be significantly lower, while neutrophil markers didn't show any change. We conclude that the neuropathic origin of the disease is confirmed at salivary level. Furthermore, the higher tryptase activity indicates a possible involvement of mast cells. The salivary neuropeptide concentration in BMS subjects, together with mast cell derived compounds, could be useful biomarkers for diagnosis and monitoring of this disease.

Burning Mouth Syndrome and Contact Dermatitis.

: Burning mouth syndrome (BMS) is a condition that remains a diagnostic challenge and is frequently difficult to treat. Rather than being a singular entity, more recent research has suggested that the diagnosis of BMS encompasses a family of syndromes. Of this family, type 3 has been identified as being related to contact dermatitis. Although this subtype has been most commonly associated with dental allergens, several food, cosmetic, and pharmaceutical products have also been identified as allergens related to the onset of BMS. Failure to identify these allergens prevents timely diagnosis and initiation of treatment for patients with BMS related to contact dermatitis. This article identifies the allergens most relevant to this type 3 and describes the commercially available allergy panels needed to ensure that all relevant allergens are included during patch testing. This study also describes approaches to diagnosis of BMS and discusses approaches to treatment based on subtypes of the condition.

Serum cytokine and T regulatory cell levels in patients with burning mouth syndrome.

BACKGROUND: Burning mouth syndrome is a disorder usually associated with an unexplained, prolonged sensation of burning inside the oral cavity. Although the etiology is unknown, neural and psychologic factors and cytokines may be implicated in the pathogenesis of burning mouth syndrome. The aim of this study was to investigate the relationship between serum cytokine and T regulatory cell levels in patients with burning mouth syndrome with regard to depression and anxiety. METHODS: Thirty patients with burning mouth syndrome and 30 matched controls participated in the study. Serum cytokine levels were measured with cytometric bead array and T regulatory cells were defined as CD4(+)CD25(+)Foxp-3(+) cells by flow cytometry. The level of anxiety and depression were analyzed by means of the Speilberger State-Trait Anxiety Inventory and Zung Self-Rating Depression Scale. Visual analogue scale was used in the quantification of burning levels of patients. RESULTS: Serum IL-2 and TNF-alpha levels were significantly decreased in patients with burning mouth syndrome compared with controls [mean 16.79 +/- 8.70 vs. 37.73 +/- 41.05 pg / ml (P < 0.05) and mean 39.09 +/- 29.40 vs. 70.83 +/- 42.44 pg / ml (P < 0.01) respectively]. CONCLUSIONS: IL-2 and TNF-alpha might play a role in burning mouth syndrome. Burning mouth syndrome may occur as a sign of predisposition to autoimmunity. Presence of low levels of CD28(+) supports the provision that BMS might be a pre-autoimmune disease.

[The value of allergy survey in a retrospective series of 40 patients with burning-mouth syndrome (stomatodynia)]. / Stomatodynies: intérêt de l'enquête allergologique dans une série rétrospective de 40 malades.

BACKGROUND: By definition, stomatodynia or burning-mouth syndrome involves oral pain with no causes being found on history taking or examination. An allergic origin is often suspected by doctors and patients alike. In this study, we attempted to assess the value of epicutaneous tests in demonstrating allergic causes for patients presenting stomatodynia. PATIENTS AND METHODS: This was a single-centre retrospective study of patients undergoing epicutaneous tests between 1996 and 2003 to screen for allergic causes of mouth pain not accounted for by any abnormalities seen during examination performed at consultations for mouth disease. RESULTS: Forty patients were included (11 male, 29 female; mean age: 58 years), and 39 were excluded. Sixteen patients presented at least one positive test, with a total of 35 positive tests in all. In decreasing order of frequency, the causes were metals, mercury derivatives (nickel salts: n=5; chrome salts: n=3; palladium salts: n=2; phenylmercuric acetate: n=2; thiomersal: n=2; cobalt salts: n=1; gold salts: n=1; mercury: n=1) and resins (acrylates: n=4). The relevance of these test results was considered probable in three cases and possible in five cases, associated with the existence of metals or resins in patients' mouths. The Peru balm test was positive in four cases but was not relevant. Tests for personal products were negative in all cases, with the exception of one case of resin from a prosthesis and one case of tixocortol pivalate. COMMENTS: Type I stomatodynia (daily occurrence with gradually increase in discomfort throughout the day) and type II stomatodynia (permanent) are not normally attributable to allergies. However, for type III stomatodynia (non-permanent, with acute episodes followed by remission), an allergy survey guided by questioning may be undertaken to determine the cause, primarily prostheses or diet. The relevance of positive test results must be interpreted with caution in view of the incidence of positive epicutaneous tests for metals and Peru balm among the general population studied.

Interleukin-1beta and serotonin transporter gene polymorphisms in burning mouth syndrome patients.

UNLABELLED: Burning mouth syndrome (BMS) is a chronic pain syndrome that encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal. Neural, psychologic, and cytokine factors may be implicated in the pathogenesis of BMS. There are no studies of genetic factors associated with psychologic behavior and cytokine pain sensitivity in BMS patients. The purpose of the present study was to investigate a possible association between functional genetic polymorphisms, +3,954 (C/T) interleukin-1beta, and the polymorphic site on promoter region of the serotonin transporter gene (5-HTTLPR) in a sample of Brazilian patients. Thirty patients affected by BMS and 31 healthy volunteers were genotyped for 5-HTTLPR and IL-1beta gene. The chi-squared test was used for statistical analysis. There was no statistical difference in 5-HTTLPR genotypes between the case and control groups (P = .60), however a significant increase was observed in the IL-1beta high production genotype CT in BMS subjects (P = .005). In conclusion, the present study shows association between BMS and IL-1beta high producer genotype. PERSPECTIVE: This article shows evidence that genetic polymorphisms associated with IL-1beta high production genotype are implicated on the pathogenesis of BMS. The modulation of IL1beta production may be an interesting tool in BMS management.

Endodontic treatment in cases of allergic reaction to rubber dam.

The prevalence and severity of latex allergies have rapidly increased recently. This article presents two cases of patients with rubber latex allergy. The patient in case A was unaware of her sensitivity to latex and presented symptoms of contact dermatitis-stomatitis during endodontic treatment. The patient in case B reported latex allergy before the initiation of the treatment and a different approach was followed. Certain aspects of latex allergy related to the endodontic treatment are discussed. Moreover, a protocol is proposed for treatment of patients with latex hypersensitivity with safety.

Burning mouth syndrome due to cadmium in a denture wearer.

We report the case of a female denture wearer who was referred to our service due to burning of the lips and tongue but with no visible oral lesions. Her biochemical data, complete blood cell count, sedimentation rate, thyroid and sex hormones were normal. Tongue culture was negative. Patch tests, performed with a panel of 20 potential denture allergens, gave positive results (+++) only to a 2% petrolatum cadmium sulfate, which was present in the denture. Removal of the denture led to the clearing up of oral symptoms in 3 days. In light of these findings, carrying out patch tests with the allergens related to denture materials should be considered in these cases.

[Role of total IgE in unspecified burning oral symptoms. Serum and salivary comparative levels in a case-control study]. / Ruolo delle IgE totali nella sintomatologia urente del cavo orale. Titolazione comparata dei livelli di IgE sieriche e salivari in uno studio caso-controllo.

BACKGROUND: Oral burning symptom is often taken into account in Oral Medicine for its high prevalence and respective management problems. The clinical evidence that exclusion from the diet of some foods, considered potentially allergenic, would relieve this symptom represented the rationale of the present study. So, the main aim was to investigate the role of the IgE-mediated pathogenesis in patients with unspecified oral burning symptoms and positivity to the challenge with some foods. METHODS: Comparative levels of total serum and salivary IgE were investigated in 97 patients referred to the Sector of Oral Medicine (University of Palermo), of whom 50/97 as a Test group, symptomatic for burning complaint and affected by burning mouth syndrome (BMS), oral lichen planus (OLP) and recurrent aphtous stomatitis (RAS) and 47/97 as Control group, non-symptomatic, matched for gender, age-decade group and affected with different oral mucosal lesions. RESULTS: In the Test group, the following results were found: total average values for serum IgE of 71.5 (SD+/-100.3; range 4-424) and for salivary IgE of 8.7 (SD+/-30.4; with range 0-218). In the Control group total average values for serum IgE were 85.8 (SD+/-210.7; range 5-1390) and for salivary IgE 20.6 (SD+/-66.6; range 2-408). Statistical evaluation of serum and salivary total IgE levels did not find any significant difference in the Test group vs controls (p>0.2) with respect to gender, age-decade or different type of oral disease with burning symptoms. Of note, in the Test group a positive correlation was found between serum IgE levels and salivary total IgE. CONCLUSIONS: On the basis of our results, no evidence of IgE-mediated allergic process can be suggested in such a generic oral burning symptom, even after a positive challenge for selective diet.

Burning mouth syndrome: patch test results from a large case series.

BACKGROUND: Burning mouth syndrome (BMS) is a burning or sore mouth in the absence of changes in the oral mucosa. It is often difficult to diagnose and treat. Numerous theories of the etiology have been suggested, including contact allergy. OBJECTIVE: To determine the clinical utility of patch testing in patients with BMS. METHODS: We retrospectively reviewed the charts of patients diagnosed with BMS who had patch testing performed between January 1, 2008, and July 31, 2012. RESULTS: Of 142 consecutive patients with BMS, 132 consented to patch testing; 89 (67%) had allergic patch test reactions. Of the patients with positive results, 66 (74%) had results that were deemed to have possible relevance. The most common allergens detected were nickel sulfate 2.5%, dodecyl gallate 0.3%, octyl gallate 0.3%, fragrance mix 8%, benzoyl peroxide 1%, and cinnamic alcohol 1%. CONCLUSIONS: Our findings suggest that contact allergy may be an etiologic factor in some patients with BMS. Patch testing is a useful investigation for BMS patients.

Immune and endocrine function in patients with burning mouth syndrome.

OBJECTIVES: Research suggests that varied etiologic factors are responsible for burning mouth syndrome (BMS). We examined the role of immune and endocrine function in the pathology of BMS. METHODS: We conducted a case-control study to evaluate immune (lymphocyte subpopulations) and endocrine (hypothalamus-pituitary-adrenal axis and sympathetic-adrenomedullary system) function in 47 female BMS patients and 47 age-matched female controls presenting at an university clinic. Psychological state was assessed with the Zung Self-Rating Depression Scale and Taylor Manifest Anxiety Scale. RESULTS: BMS patients were significantly more anxious than controls (P=0.011). Plasma adrenaline level was significantly lower (P=0.020) in BMS patients than in controls, and linear regression analysis of all patients combined revealed that depression level was significantly positively associated with plasma noradrenaline and cortisol levels (P=0.002 and 0.001, respectively). However, as compared with controls, BMS patients had a significantly lower CD8(+) cell count (P<0.001) and a significantly higher CD4/CD8 ratio (P=0.002). Discriminant analysis revealed that CD8(+) cell count and CD4/CD8 ratio were independent variables that distinguished BMS patients from controls. DISCUSSION: The immunoendocrine system is substantially involved, and may have a key role, in the mechanism of chronic pain in BMS patients. Immune function was significantly and specifically suppressed in BMS, although the hypothalamic-pituitary-adrenal axis and sympathetic nervous system were predominantly activated by psychological stress that was not specific to BMS.

Soluble CD14 and toll-like receptor-2 are potential salivary biomarkers for oral lichen planus and burning mouth syndrome.

Oral lichen planus (OLP) and burning mouth syndrome (BMS) are chronic conditions affecting the oral mucosa characterized by pain and burning sensation. Saliva plays a significant role in the maintenance of physical and functional integrity of normal oral mucosa. Identification of potential "salivary biomarkers" for early diagnosis and/or monitoring of human diseases is being explored. We investigated the soluble forms of innate immune associated proteins CD14 and toll-like receptor-2 in unstimulated whole saliva (UWS) as potential biomarkers for OLP and BMS. Our results suggest that the levels of sCD14 and sTLR-2 in UWS were upregulated in OLP and BMS respectively. In addition, oral epithelial cells in the saliva of patients with OLP and BMS exhibited elevated levels of CD14 mRNA and decreased levels of TLR-2 mRNA. Interestingly, presence of co-existent oral candidiasis nullified these changes.

Salivary interleukin-6 and tumor necrosis factor-alpha in patients with burning mouth syndrome.

Burning mouth syndrome (BMS) is characterized by burning symptoms on the clinically healthy oral mucosa. To date, etiology of BMS is still unknown. We hypothesized that maybe inflammation which is not clinically apparent might lead to burning symptoms which would then result in altered cytokine profile. In the 28 female patients with BMS (age range 48-80 years, mean 64.05 years) and 28 female controls (age range 40-75 years, mean 63.82 years) by use of enzyme-linked immunosorbent assay, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were determined. Statistical analysis included use of independent sample t-test and P < 0.05 was considered as significant. Our results show no significant differences between patients and controls regarding salivary IL-6 and TNF-alpha.

[Seasonal burning palate in allergy against grass pollen]. / Saisonales Gaumenbrennen bei Allergie gegen Gräserpollen.

An immediate type I allergy elicited by IgE antibodies against pollen of grasses and cereals was demonstrated as the rare cause of palatinal stomatopyrosis (burning palate). The casual relationship was suggested through history and proven by skin, radioallergosorbent and exposition tests.

Peanut sensitivity as a cause of burning mouth.

A patient with a history of a burning tongue together with discomfort of the labial and buccal mucosae was given an elimination diet and skin patch tests to determine the allergen in her diet. The patient was identified as being intolerant of an aqueous peanut extract. Three allergens in peanut butter were identified, the one with greatest reactivity being a heat-stable, water-soluble, nonglycosylated protein with a molecular weight in excess of 10 kD. Modification of her diet has resulted in resolution of the oral problem.

Oral allergy syndrome induced by chestnut (Castanea sativa)

BACKGROUND: Oral allergy syndrome is a distinctive type of allergy to food resulting from direct contact between food and the oral mucosa. Normally, it affects patients who are allergic to pollens. It can be challenged by testing for hypersensitivity to fresh fruit or vegetables in well-known associations. Oral allergy syndrome rarely occurs in patients with other types of allergies, or to food not associated with pollens. Only occasionally does chestnut cause hypersensitivity. There are only a few reported cases, depending on cross-reactivity in previously latex-hypersensitive patients. Oral allergy syndrome to chestnut in a patient with respiratory allergy to Dermatophagoides is therefore unusual and worth reporting. OBJECTIVES: To describe the clinical features and their differences from previously reported cases and to analyze the techniques and methodologic problems related to in vivo and in vitro diagnosis. METHODS: Case report. Skin tests with commercial and freshly made extracts and by the prick-by-prick method. Challenge test. Specific IgE antibody assay. Prausnitz-Küstner reaction. RESULTS: The challenge with fresh food confirmed an oral allergy syndrome to chestnut. Clear symptoms of rhinoconjunctivitis and asthma set in as well. Skin tests with several commercial extracts and the prick-by-prick test were negative and so was specific IgE assay in serum by RAST and other immunoenzymatic methods. Skin prick test with a freshly prepared extract of fresh chestnut and the passive transfer reaction were positive. CONCLUSIONS: The case of oral allergy syndrome to chestnut reported here appears to be a manifestation of immediate IgE-dependent hypersensitivity.

Type 3 burning mouth syndrome: psychological and allergic aspects.

A subgroup of patients with burning mouth syndrome was investigated. The clinical history of these patients differed from the norm in that symptoms were intermittent and affected unusual sites. In addition, routine investigations were supplemented with a more detailed psychological evaluation than reported previously and also a possible allergic component was studied by patch testing. The study has shown that this subgroup differs from burning mouth syndrome patients overall in that emotional instability and allergic reactions, particularly to food additives, are of etiological significance and require to be taken into consideration in terms of patient management.