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

Abstract

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.

Keywords

Burning Mouth Syndrome cytokines systematic review

Introduction

“Burning Mouth Syndrome (BMS) is the intra-oral burning or dysesthetic sensation, recurring daily for more than 2 hours/day for more than 3 months, without any clinically evident causative lesion” (1). The common symptoms include pain, burning and altered taste sensation that occur bilaterally in the oral cavity and predominantly involve the anterior two-thirds of the tongue (2,3). Despite the extensive research, the mystery of diagnosing and thereby treating BMS remains unsolved (4). Patients presenting with BMS pose one of the biggest challenges to dentists and oral health care professionals (5).

Cytokines are a group of proteins secreted by immune cells responsible for regulation of host responses to infection, immune modulation, inflammation, and trauma. Pro-inflammatory cytokines worsen the disease, whereas anti-inflammatory cytokines contain the inflammatory process and promote healing. Stress is a major determinant of cytokine levels in the body since cytokines are associated with major neurotransmitters (6). Cytokines play a major role in damaged tissue repair, in the development and spread of cancer, in the control of cell replication and apoptosis, and in the fine-tuning of immune reactions (7). Cytokine receptor activation and hence alteration in the cytokine balance has been proposed to play a major role in neuronal dysfunction and etiopathogenesis of stress (8).

The etiopathology of BMS is ambiguous. However, it has been proposed in studies that an interplay of local, systemic and psychological factors contribute to pathogenesis of BMS (9,10). In their study, Suh et al. reported that BMS is a sub-clinical inflammation that results in a change in cytokine levels, causing symptoms such as burning and pain (11). Cytokines act as potential neuromodulators in the processing of nociceptive signals causing neuropathic pain and/or hyperalgesia. They mediate their functions through glia proliferation, axonal regeneration and proinflammation (12). Galli et al. quantitatively assessed the role of psychological factors in BMS (13). However, to date, to the best of our knowledge there is no published systematic review that has evaluated the levels and role of cytokines in the etiopathogenesis of BMS. Recent cross-sectional studies highlight the significance of cytokines in BMS (12,14). For instance, in their study De Souza et al. concluded that some of the proinflammatory cytokines such as the levels of interleukin (IL)-6 are higher and those of tumour necrosis factor alpha (TNFα) are lower in patients with BMS when compared with healthy controls (HC) (14). However, Chen et al. proposed that serum levels of IL-6 in BMS are lower when compared with HC (12). On the other hand, Barry et al. concluded that levels of TNFα and IL-6 are comparable between BMS and HC (15). The findings with regards to cytokine profile in BMS and HC are conflicting, and a systematic review is deemed necessary to compare the levels of cytokines and to discuss their role in the etiopathogenesis of BMS.

Therefore, the aim of the current systematic review is to evaluate and compare the overall inflammatory burden assessed in terms of cytokine levels in adult patients suffering from BMS and healthy controls.

Materials and methods

Protocol registration

This review was registered at the National Institute for Health Research PROSPERO, International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO, registration number CRD42018114525 on 5 December 2018. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (17) were followed. The following focused PECO question was formulated:

In adult patients (Patients) suffering from BMS (Exposure), what is the overall inflammatory burden assessed in terms of cytokine levels (Outcome) when compared with healthy controls (Control)?

Search strategy

The authors (JK and ZA) searched the PubMed (National Institutes of Health, Bethesda) and EMBASE from November 1986 to November 2018 for appropriate articles addressing the focused question. Literature was thoroughly searched for identification of papers that compared the levels of cytokines between BMS and healthy controls. The electronic database search was carried out using varying combinations of the following terminology: (a) “burning mouth syndrome” (b) “oral dysesthesia” (c) “glossodynia” (d) “stomatopyrosis” (e) 1 or 2 or 3 or 4 (f) “Cytokines” (g) “Interleukins” (h) 6 or 7, biomarkers.

Selection criteria

Screening and assessment of articles was independently carried out by two reviewers (JK and SM). Any disagreement among the authors regarding study selection or exclusion was resolved through discussion and/or by consulting a third reviewer (ZA). The eligibility criteria included: i) Cross sectional, case-control and/or retrospective studies in human adult patients; ii) study samples clinically diagnosed with BMS; iii) evaluation of cytokines in patients with BMS in comparison with HC using any type of assay method; and iv) articles published in the English language only. The exclusion criteria included animal studies, studies involving treatment intervention, in-vitro analyses, case reports, case series, abstracts, unpublished articles and letters to the editor.

Data extraction

Data from the included studies was extracted individually by two reviewers (JK and ZA). The information from the included studies was tabulated according to the following sections: Study designs, subject demographics, gender distribution, additional clinical parameters assessed, cytokines studied, sample and assay type and main outcomes (Table 1). All the information obtained was based on the focused question outlined for the present systematic review. The reviewers cross-checked all extracted data. Any differences in opinion were resolved by discussion until consensus was reached.

Quality assessment

The Newcastle-Ottawa Quality Assessment scale (NOS), a validated tool for convenient assessment of the quality of observational and nonrandomized studies was used to evaluate the quality of the included studies (18). According to this scale, the studies were evaluated under three broad perspectives: The selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest for included studies respectively (19).

Data analysis

Meta-analyses were not possible in the present study due to significant heterogeneity in the methods and presentation of the data.

Results

Study selection

Out of a total of 1160 search results, 17 were duplicate studies and were removed (K = 0.71). Out of 1143 studies, 1125 were excluded as they were found to be irrelevant to the focused question. Eighteen studies were selected for full text review following initial screening of titles and abstracts. A full text review resulted in the exclusion of another 10 studies that did not meet the inclusion criteria and finally a total of eight studies (6,11,12,14,15,20 –22) were included in the current review (K = 0.92). All the studies in this review were carried out at registered medical facilities (i.e. clinical/healthcare setups or universities). Figure 1 reports the PRISMA flow diagram of the selection process and excluded articles with reasons.

Figure 1.

PRISMA flow diagram for studies retrieved through the searching and selection process.

Characteristics of the selected publications

From a total of eight studies, seven were case-control studies (6,11,12,15,20 –22) and one was a cross-sectional study (Table 2) (14). Two of the studies were carried out in Turkey (6,21) and there was one study each in Ireland (15), the USA (20), Brazil (14), South Korea (11), China (12), and Croatia (22), respectively. The present review included a total of 228 BMS patients and 193 healthy controls. The mean age of BMS patients and healthy controls ranged from 49.0 years to 62.13 years and 49.0 years to 65.1 years, respectively. The percentage of females ranged from 63% to 100%. Five of the included studies used saliva as their sample (11,14,20 –22) while one study (15) used plasma and two studies used serum as their sample type (6,12). Enzyme-linked immunosorbent assay (ELISA) was used to quantify biomarkers in all the included studies. In addition to the cytokine levels, almost all the studies assessed pain and depression using different standardized calibrated scales. The visual analog scale (VAS) was used to measure the pain intensity in five studies (6,12,14,15,20), whereas depression was evaluated with the help of various tools including the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) (15), the Mini International Neuropsychiatric Interview Plus (MINI-plus) (14) and Hamilton Depression Rating Scale (HRSD) (12), respectively. Two of the studies objectified depression using the Zung Self-Rating Depression Scale and Speilberger State-Trait Anxiety Inventory (SAI-TAI) (6,21).

Table 1.

Cytokine assessment of study groups.

Authors, year	Study groups	Cytokine[s] evaluated	Sample type	Type of assay	Main outcomes
Barry et al. 2018 (15)	BMS: 10 HC: 10	IL-8, IL-4, IL-2, IL-12p70, IL-13, IFN-γ, IL-6, IL-10, TNF–α, IL-1β	Plasma	ELISA	IL-8 increased in BMS compared to HC IL-4, IL-2, IL-12p70, IL-13, IFN-γ, IL-6, IL-10, TNF–α and IL-1β comparable between the two groups
Ji et al. 2017 (20)	BMS: 10 HC: 10	IL-18	Saliva	ELISA	IL-18 increased in BMS compared to HC
De Souza et al. 2015 (14)	BMS: 30 HC: 32	TNF-α, IL-6, IL-10	Saliva	ELISA	IL-6 increased and TNF-alpha decreased in BMS compared to HC
Suh et al. 2009 (11)	BMS: 40 HC: 20	IL-1b, IL-6, IL-8, and TNF-a	Saliva	ELISA	No difference between cases and controls
Pekiner et al. 2009 (21)	BMS: 30 HC: 30	IL-2 IL-6	Saliva	ELISA	No difference between cases and controls
Pekiner et al. 2008 (6)	BMS: 30 HC: 30	IL-2, IL-4, IL-6, IL-10, TNF-a IFNγ	Serum	ELISA	IL-2 and TNF-a were lower in BMS compared to HC. No difference in IFN, IL-4, IL-6 and IL-10 in cases and controls
Chen et al. 2007 (12)	BMS: 48 HC: 31	IL-6	Blood	ELISA	IL-6 is lower in BMS compared to HC
Simcic et al. 2006 (22)	BMS: 30 HC: 30	IL-2 IL-6	Saliva	ELISA	IL-2 and IL-6 increased in BMS compared to controls

BMS: burning mouth syndrome; HC: healthy control; IL: interleukin; IFN: interferon; TNF:tumor necrosis factor.

Cytokine levels among BMS patients

A total of eight cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-1ß, TNF-α and gamma interferon showed differential expression when their levels were evaluated and compared in BMS patients and healthy controls (6,11,12,14,15,20 –22). Seven out of eight studies evaluated IL-6 (6,11,12,14,15,21,22) while four studies quantified IL-2 (6,15,21,22) and three studies evaluated TNF-α (6,11,14), respectively. Three out of eight studies measured IL-10 (6,11,14,15), whereas two studies evaluated IL-4 (6,15), IL-8 (11,15), IL-1ß (11,15) and gamma interferon (11,15) levels, respectively.

Main outcomes of the study

The data of the present systematic review could not be quantitatively analyzed due to different presentations of the results, including graphs (15,20), or because the quantities were expressed in mode, median and/or mean without standard deviation (14,21). Therefore, the findings of the present study are reported in narrative manner.

IL-2

Out of the four studies (6,15,21,22) evaluating IL-2 levels, Pekiner et al. (6) reported that subjects in the control group had significantly higher mean values for IL-2 compared with BMS patients. On the contrary, Simcic et al. (22) reported that the average value of IL-2 concentration was significantly higher in the group of patients with BMS compared to the control group. The other two authors concluded that no statistical difference in the IL-2 levels was observed between the two groups (15,21).

IL-6

Four out of seven studies evaluating IL-6 reported comparable results between BMS and healthy controls (6,11,15,21). De Souza et al. and Simcic et al. concluded that levels of IL-6 are higher in BMS (14,22), whereas Chen et al. revealed that the levels were significantly lower in BMS compared to healthy controls (12).

TNF-α

Barry et al. and Suh et al. reported comparable levels of TNF-α between BMS and controls (11,15). On the contrary, De Souza et al. and Pekiner et al. reported lower levels of TNF-α in patients with BMS (6,14).

IL-8

Barry et al. (15) reported IL-8 to be significantly raised in BMS, whereas Suh et al. (11) reported comparable results between BMS and controls.

IL-18

Ji et al. reported a statistically significant increase in the levels of IL-18 in BMS patients compared with healthy controls (20).

IL-4, IL-10, IL-1ß, Gamma interferon

All studies reported no significant difference in the levels of IL-4, IL-10, IL-1ß and gamma interferon between BMS and controls (6,11,12,14,15,20 –22).

Risk of bias across studies

Study quality as assessed by the NOS varied considerably across the studies, ranging from 4/9 to 8/9. Table 3 presents the quality assessment of included studies. Four studies were of good quality (6,14,21,22) whereas the four other studies were of moderate quality (11,12,15,20).

Table 2.

General description of the included studies.

Author/year of publishing	Study design, country	Study group/demographics: Total number of patients; mean age in years (age range); F/M	Additional clinical parameter	Cytokines studied
Barry et al. 2018 (15)	Case control, Ireland	BMS: n = 10; 57.6 (NA); 10/0 Controls: n = 10; 52.9 (NA); 10/0	VAS QIDS-SR16	IL-8, IL-4, IL-2, IL-12p70, IL-13, IFN-γ, IL-6, IL-10, TNFα, IL-1β
Ji et al. 2017 (20)	Case control, USA	BMS: n = 10; NA; NA Controls: n = 10; NA; NA	VAS	IL-18
De Souza et al. 2015 (14)	Cross-sectional, Brazil	BMS: n = 30; 62.13 (NA); 29/1 Controls: n = 32; 61.59 (NA); 31/1	VAS VDS MINI-Plus	TNF-α, IL-6, IL-10
Suh et al. 2009 (11)	Case control, South Korea	BMS: n = 40; 61.6 (NA); 40/0 Controls: n = 20; 65.1 (NA); 20/0	Gingival Index	IL-1b, IL-6, IL-8, and TNFα
Pekiner et al. 2009 (21)	Case control, Turkey	BMS: n = 30; 54.23 (NA); 19/11 Controls: n = 30; 50.87 (NA); 21/9	Zung Self-Rating Depression Scale SAI-TAI	IL-2 IL-6
Pekiner et al. 2008 (6)	Case control, Turkey	BMS: n = 30; 54.23 (NA); 19/11 Controls: n = 30; 50.87 (NA); 21/9	Zung Self-Rating Depression Scale SAI-TAI VAS	IL-2, IL-4, IL-6, IL-10, TNFα, IFNγ
Chen et al. 2007 (12)	Case control, China	BMS: n = 48; 49 (26–80); 39/9 Controls: n = 31; 49 (30–61); 25/6	VAS HRSD	IL-6
Simcic et al. 2006 (22)	Case control, Croatia	BMS: n = 30; NA (55–65); NA Controls: n = 30; NA (55–65); NA	None	IL-2 IL-6

BMS: burning mouth syndrome; HC: healthy control; F/M: female/male; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; UWS: unstimulated whole saliva; SWS: stimulated whole saliva; NA: not applicable; ELISA: enzyme-linked immunosorbent assay; VAS: visual analog scale; HRSD: Hamilton Rating Scale for Depression; QIDS-SR16: Quick Inventory of Depressive Symptomatology-Self-Report.

Table 3.

Quality of studies assessed by Newcastle Ottawa Scale.

Authors	Selection	Comparability	Exposure	Score	Quality
Barry et al. (15)	⋆⋆⋆	⋆	⋆	5	Moderate
Ji et al. (20)	⋆⋆⋆	⋆	⋆⋆	6	Moderate
De Souza et al. (14)	⋆⋆⋆⋆	⋆	⋆⋆	7	High
Suh et al. (11)	⋆⋆	⋆	⋆	4	Moderate
Pekiner et al. (21)	⋆⋆⋆⋆	⋆⋆	⋆⋆	8	High
Pekiner et al. (6)	⋆⋆⋆⋆	⋆⋆	⋆⋆	8	High
Chen et al. (12)	⋆⋆	⋆	⋆⋆	5	Moderate
Simcic et al. (22)	⋆⋆⋆	⋆	⋆⋆⋆	7	High

Discussion

This review aimed to systematically evaluate the levels of cytokines among patients suffering from BMS and healthy controls, and to further conclude whether cytokines play a part in the etiopathogenesis of BMS. To the best of our knowledge, this is the first systematic review that has evaluated cytokines and their contribution to BMS pathogenesis. However, the outcomes of the present systematic review should be interpreted with extreme caution for several reasons.

There are various studies that postulate the underlying etiopathogenesis of BMS as an amalgamation of inflammation, psychological disturbance and neuropathic derangement (5,23). However, few of the authors have suggested only one of these factors to be solely responsible for the pathogenesis of BMS. Research suggests that conditions altering the psychological well-being of patients, including depression, stress and chronic anxiety, cause an alteration in the production of adrenal steroids (24). This is turn causes dysregulation in the production of a few precursors required in the synthesis of neuroactive steroids that are present in skin, mucosa, and the nervous system (25). The outcome is permanent neurodegenerative alterations in small nerve fibers of the oral mucosa and/or some brain areas involved in oral somatic sensations, resulting in irreversible neuropathic change and hence the symptoms of pain, burning, dysgeusia, and xerostomia associated with BMS (26). Several studies have highlighted the fact that neuropathy is concomitant with BMS (27 –29). By providing evidence of diffuse degeneration of epithelial and sub-papillary nerve fibers in the anterior two-thirds of the tongue, Lauria et al. demonstrated that BMS is associated with small-fiber sensory neuropathy (30). Another study reported hypofunction of Aδ fibers in the distribution of the lingual nerve of individuals diagnosed with BMS in addition to hypofunction of C-fibers, proving BMS represents a generalized neuropathy (31).

The etiopathogenesis of BMS has been widely attributed to subclinical inflammation, which has been measured via different cytokine expression levels (14,15,22). However, whether disrupted cytokine levels are a cause or an effect of the disease process in BMS is still undecided. A disruption in the balance between proinflammatory and anti-inflammatory cytokines can either enhance or dampen inflammatory reaction and immune response (32). IL-2 stimulates secretion of proinflammatory cytokines such as IL-1, TNF-α and TNF-β, inducing infiltration and activation of immune cells that result in recruitment of greater numbers of macrophages, mast cells and T-lymphocytes, creating a vicious cycle that makes the inflammatory state constant and chronic. Proinflammatory cytokines are associated with nociceptive signaling and are usually increased in neuropathic pain disorders (33) including BMS (15).

IL-6 is a pleotropic cytokine that influences the antigen-specific immune responses and inflammatory reactions, in addition to modulating pain and inducing hyperalgesia (22). IL-6, along with IL-1 and TNF-α, is a potent modulator of corticotropin-releasing hormone, which is responsible for increased hypothalamic-pituitary-adrenal axis activity leading to an increase in adrenocorticotropic hormone and cortisol, eventually resulting in a major depression event. Pain due to subclinical inflammation and depression is a major component of BMS. Persistently elevated cytokine levels cause a permanent alteration in neurotransmitter function, leading to neuropsychiatric dysfunction, particularly depression (34). On the other hand IL-18, a pro-inflammatory cytokine, acts as an inflammatory mediator by accelerating the immune response via recruitment of neutrophils, macrophages and further acting upon other cytokines like IL-8 and TNF-α (35). In their study, Ji et al. reported elevated levels of IL-18 as most likely contributing to the etiopathogenesis of BMS (20). However, some studies included in this review failed to find any association between deranged cytokine levels and BMS pathogenesis (11,15,21). Two studies reported a negative correlation between BMS and cytokine signature (6,12), implying that inflammation does not play a significant role in BMS etiopathogenesis. It may be hypothesized that psychological and neuropathic disorders could be held responsible as the precipitating factors in the disease initiation. These authors have in common drawn a conclusion that in order to assess BMS development a variety of causative factors need to be considered. The findings of these studies prove to be of little help in designating cytokines as biomarkers for the diagnosis of BMS.

Apart from biochemical analysis, clinical parameters like pain and depression were also assessed by means of calibrated scales and questionnaires. All the authors unanimously concluded that BMS is accompanied by pain of variable intensity. However, whether depression is a cause or an effect of BMS is yet to be affirmed. According to Barry et al. (15), cytokines are elevated in patients with depressive disorders and chemokines/cytokines play a vital role in the development of neuropsychiatric disorders via neural serotonin-catecholamine signaling. Suh et al. (11) measured the gingival index in order to assess the blood contamination of saliva and found no significant difference between patients and controls.

Like any other study, the present study has a few limitations that need to be considered. Firstly, in our present review we have included studies that were published in the English language, which in our view might have resulted in publication bias and loss of relevant studies published in other languages (36,37). The small number of studies eligible for the qualitative analysis may not be sufficient to give us clear results. The number of studies for the quantitative meta-analysis was found to be further reduced because we failed to obtain the means and standard deviations even after correspondence with the authors. In order to extract maximum data for meta-analysis, the corresponding authors of all the articles were contacted where the data was presented in graphical form or there was a lack of data. However, the response rate was 0%. Although IL-6 was the most commonly studied cytokine, a noteworthy fact was that all the included studies evaluated different cytokines. Moreover, the fact that half of the studies had moderate quality reflects a questionable outcome. Additionally, the sample type was not the same in all studies, which could have had a significant impact on the final outcome of the current review while interpreting the results. The different body fluids used in studies could have given skewed outcomes. The oral cavity represents a distinct environmental niche and immune biomarkers present in saliva are influenced by processes of local immunity, leading to a possible discrepancy in the cytokine levels in saliva compared to other body fluids (38,39).

The available studies on BMS and cytokine levels are sparse and variable. Therefore, further high-quality studies are warranted to address the interplay of psychological dimensions, neuropathic involvement and subclinical inflammation in BMS. Since BMS has a severe adverse psychological, physical and social impact on life, a collaborative effort by dentists, oral surgeons and clinical psychologists is needed for timely diagnosis and effective management of the condition.

Conclusion

The available studies on BMS and cytokine levels are sparse and variable. From the present review, it remains debatable whether increased or decreased cytokine levels contribute to the etiopathogenesis of BMS. Therefore, further high-quality studies are warranted to address the interplay of psychological dimensions, neuropathic involvement and subclinical inflammation in BMS.

Footnotes

Article highlights

The expression of cytokines and their role in the etiopathogenesis of BMS were investigated.

A total of eight studies were included in the current review.

Four studies were of high and four of moderate quality.

Whether up-regulation or down-regulation of specific cytokines contribute to the etiopathogenesis of BMS remains debatable.

Further cross-sectional studies with a larger sample size and assessing a wider array of cytokines are warranted in order to obtain strong conclusions.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Olesen

; Headache Classification Committee of the International Headache Society (IHS) . The International Classification of Headache Disorders, Abstracts. Cephalalgia 2018; 38: 1–211.

Feller

Fourie

Bouckaert

, et al. Burning Mouth Syndrome: Aetiopathogenesis and principles of management. Pain Res Manag 2017; 2017: 1926269. DOI: 10.1155/2017/1926269 .

Aggarwal

Panat

. Burning mouth syndrome: A diagnostic and therapeutic dilemma. J Clin Exp Dent 2012; 4: e180–e185. .

Liu

Kim

Yoo

, et al. Burning mouth syndrome: A systematic review of treatments. Oral Dis 2018; 24: 325–334.

Ritchie

Kramer

. Recent advances in the etiology and treatment of burning mouth syndrome. J Dent Res 2018; 97(11): 1193–1199.

Pekiner

Demirel

Gümrü

, et al. Serum cytokine and T regulatory cell levels in patients with burning mouth syndrome. J Oral Pathol Med 2008; 37: 528–534.

Foster

. The functions of cytokines and their uses in toxicology. Int J Exp Pathol 2001; 82: 171–192.

Di Giannantonio M, Frydas S, Kempuraj D, et al. Cytokines in Stress. Int J Immunopathol Pharmacol 2005; 18: 1–5.

Perno

. Burning mouth syndrome. J Dent Hyg 2001; 75: 245–252. quiz, 252–243, 255.

10.

Spanemberg

de Rivera Campillo

Salas

, et al. Burning mouth syndrome: Update. Oral Health Dent Manag 2014; 13: 418–424.

11.

Suh

K-I

Kim

Y-K

Kho

H-S

. Salivary levels of IL-1β, IL-6, IL-8, and TNF-α in patients with burning mouth syndrome. Arch Oral Biol 2009; 54: 797–802.

12.

Chen

Xia

Lin

, et al. Serum interleukin-6 in patients with burning mouth syndrome and relationship with depression and perceived pain. Mediators Inflamm 2007; 2007: 45327. DOI: 10.1155/2007/45327 .

13.

Galli

Lodi

Sardella

, et al. Role of psychological factors in burning mouth syndrome: A systematic review and meta-analysis. Cephalalgia 2017; 37: 265–277.

14.

de Souza

Kummer

Silva

, et al. The association of openness personality trait with stress-related salivary biomarkers in burning mouth syndrome. Neuroimmunomodulation 2015; 22: 250–255.

15.

Barry

O'Halloran

McKenna

, et al. Plasma IL-8 signature correlates with pain and depressive symptomatology in patients with burning mouth syndrome: Results from a pilot study. J Oral Pathol Med 2018; 47: 158–165.

16.

Maia

Antonio

. Systematic reviews in dental research. A guideline. J Clin Pediatr Dent 2012; 37: 117–124.

17.

Moher

Liberati

Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009; 151: 264–269.

18.

Stang

. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603–605.

19.

Margulis

Pladevall

Riera-Guardia

, et al. Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: The Newcastle–Ottawa scale and the RTI item bank. Clin Epidemiol 2014; 6: 359–368 .

20.

Diep

Liu

, et al. Potential protein biomarkers for burning mouth syndrome discovered by quantitative proteomics. Mol Pain 2017; 13: 1744806916686796.

21.

Pekiner

Gümrü

Demirel

, et al. Burning mouth syndrome and saliva: Detection of salivary trace elements and cytokines. J Oral Pathol Med 2009; 38: 269–275.

22.

Simcic

Pezelj-Ribaric

Gržic

, et al. Detection of salivary interleukin 2 and interleukin 6 in patients with burning mouth syndrome. Mediators Inflamm 2006; 2006: 54632. DOI: 10.1155/MI/2006/54632. .

23.

Zakrzewska

Buchanan

. Burning mouth syndrome. BMJ Clin Evid 2016; 2016: 1301 .

24.

Kim

Y-K

K-S

Myint

A-M

, et al. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64: 277–284.

25.

Woda

Dao

Gremeau-Richard

. Steroid dysregulation and stomatodynia (burning mouth syndrome). J Orofac Pain 2009; 23: 202–210. .

26.

das Neves de Araújo Lima

Barbosa

dos Santos

ACS

, et al. Comparative analysis of psychological, hormonal, and genetic factors between burning mouth syndrome and secondary oral burning. Pain Med 2016; 17: 1602–1611.

27.

de Souza Moura

dos Reis Ferreira

DosSantos

, et al. Changes in the vibration sensitivity and pressure pain thresholds in patients with burning mouth syndrome. PloS One 2018; 13: e0197834.

28.

Forssell

Jääskeläinen

Tenovuo

, et al. Sensory dysfunction in burning mouth syndrome. Pain 2002; 99: 41–47.

29.

Zhang

Fan

, et al. Thermal and mechanical quantitative sensory testing in Chinese patients with burning mouth syndrome – a probable neuropathic pain condition?. J Headache Pain 2015; 16: 84.

30.

Lauria

Majorana

Borgna

, et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain 2005; 115: 332–337.

31.

Puhakka

Forssell

Soinila

, et al. Peripheral nervous system involvement in primary burning mouth syndrome – results of a pilot study. Oral Dis 2016; 22: 338–344.

32.

Rhodus

Cheng

Myers

, et al. A comparison of the pro-inflammatory, NF-κB-dependent cytokines: TNF-alpha, IL-1-alpha, IL-6, and IL-8 in different oral fluids from oral lichen planus patients. Clin Immunol 2005; 114: 278–283.

33.

Opree

Kress

. Involvement of the proinflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 but not IL-8 in the development of heat hyperalgesia: Effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 2000; 20: 6289–6293.

34.

Felger

Lotrich

. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neurosci 2013; 246: 199–229.

35.

Banu

Jabir

Mohan

, et al. Correlation of Toll-like receptor 4, interleukin-18, transaminases, and uric acid in patients with chronic periodontitis and healthy adults. J Periodontol 2015; 86: 431–439.

36.

Grégoire

Derderian

Le Lorier

. Selecting the language of the publications included in a meta-analysis: Is there a Tower of Babel bias?. J Clin Epidemiol 1995; 48: 159–163.

37.

Moher

Fortin

Jadad

, et al. Completeness of reporting of trials published in languages other than English: Implications for conduct and reporting of systematic reviews. Lancet 1996; 347: 363–366.

38.

Morales-Rojas

Viera

Morón-Medina

, et al. Proinflammatory cytokines during the initial phase of oral mucositis in patients with acute lymphoblastic leukaemia. Int J Clin Pediatr Dent 2012; 22: 191–196.

39.

Williamson

Munro

Pickler

, et al. Comparison of biomarkers in blood and saliva in healthy adults. Nurs Res Pract 2012; 2012: 246178. DOI: 10.1155/2012/246178 .