TNF-α levels and presence of SNP-308G/A of TNF-α gene in temporomandibular disorder patients

ABSTRACT Introduction: Temporomandibular disorder (TMD) refers to a group of conditions that compromise the harmonious movement and function of the temporomandibular joint, masticatory muscles, and associated structures. The etiopathogenesis of TMD is multifactorial but not well-understood, with the role of genetic factors still being unclear. Objective: This review aims to summarize the results of studies that evaluated TNF-α levels and the -308G/A TNF-α polymorphism in TMD patients. This study emphasizes the importance of a more selective treatment involving TNF-α inhibitors that can potentially reduce inflammation and pain, and improve quality of life. Methods: The MEDLINE/PubMed database, Cochrane Library, and Web of Science database were searched for case-control studies published until September 2020 that compared levels of TNF-α or presence of its -308G/A polymorphism in TMD patients and healthy individuals. Results: Six case-control studies were identified with a total of 398 TMD patients, aged between 12 and 78 years. The control group consisted of 149 subjects, aged between 18 and 47 years. The occurrence of TMD was predominant in females. Majority of studies found high TNF-α levels in TMD patients, compared to the control group. One of these studies found a positive correlation between the GA genotype and the development of TMD. Conclusion: Majority of the TMD patients showed elevated TNF-α levels, and a possible explanation for this could be the presence of the -308G/A polymorphism.


INTRODUCTION
Temporomandibular disorder (TMD) refers to a group of conditions that compromise the harmonious movement and function of the temporomandibular joint (TMJ), masticatory muscles, and associated structures. 1 Chronic TMD commonly occurs as orofacial pain, and is considered a public health problem. 2 It occurs more frequently and severely in women than in men. 3 Its prevalence in the Brazilian population is between 4% and 12%. 4 The most common symptoms of TMD are limited mandibular movements, TMJ sounds (click and crepitus), headache, and pain. 5 The etiopathogenesis of TMD is multifactorial and involves joint and muscle trauma, anatomical factors, psychosocial aspects, and sensitization of nociceptive pathways, but the role of genetic factors in the etiology of TMD remains unclear and needs to be investigated. 6 As TMD is caused by multiple factors, several forms of treatment are available, such as occlusal splints, counseling, physical therapy, 7 surgery, acupuncture, botulinum toxin injection, pharmacotherapy, 8 orofacial myofunctional therapy, and low laser therapy. 9 Pharmacotherapy involves anti-inflammatory agents, analgesics, muscle relaxants, and in certain situations, tricyclic antidepressants; however, in certain cases, these therapeutics are not successful and patients suffer with persistent pain. Tumor necrosis factor alpha (TNF-α) is an important pro-inflammatory cytokine that contributes considerably to inflammation and immune response. 11 TNF-α is mainly produced by macrophages, lymphocytes, and trophoblastic cells. 12 The single nucleotide polymorphism (SNP) -308G/A TNF-α rs1800629 is characterized by the replacement of guanine (G) with adenine (A) in the promoter region of the gene, which leads to a greater production of this interleukin. 13 Only a few studies have evaluated the presence of interleukins and genetic polymorphisms in TMD patients, but they have pro-

ELIGIBILITY CRITERIA
Only those case-control studies that evaluated levels of TNF-α or its -308G/A polymorphism in TMD patients were included.
Studies focusing on other polymorphisms and/or interleukins, and studies that did not draw comparison to a control group were excluded.

INFORMATION SOURCES AND SEARCH STRATEGY
The MEDLINE/PubMed database, Cochrane Library, and Web

DATA COLLECTION PROCESS
The following variables were collected: author, type of study, number of patients, number of healthy individuals, gender, mean age, TNF-α levels, and the presence of the -308G/A polymorphism of this interleukin.

RESULTS
All reports considered in this review are case-control studies that measured TNF-α concentrations or detected the presence of -308G/A polymorphism in TMD patients. Six studies were identified, with a total of 398 TMD patients, aged between 12 and 78 years, whereas the control group consisted of 149 subjects, aged between 18 and 47 years. Details of the six studies included in this review are described in Table 1 21 Five studies evaluated TNF-α levels in TMD patients, [15][16][17][18][19] which were expressed as mean concentration ± SD (Table 2), and one study detected the presence of the -308G/A polymorphism of this interleukin 20 ( Table 3). Most of these studies found higher TNF-α levels in the TMD patients group than in the healthy individuals. 16,[18][19] Campello CP, Lima ELS, Fernandes RSM, Porto M, Muniz MTC -TNF-α levels and presence of SNP-308G/A of TNF-α gene in temporomandibular disorder patients  reported in other studies. 4,9,22,23 Of the six studies analyzed, five evaluated TNF-α concentrations and one investigated the presence of the -308G/A polymorphism, which is a G to A mutation at the -308 position in the promoter region, and is associated with higher levels of TNFα. 13 Despite the fact that these studies are difficult to compare because different fluids were used to measure the concentration of this interleukin, all lead us to reflect on the possibility of developing a more targeted treatment. Two articles 16   Similarly, Lee et al. 17 found higher TNF-α levels in patients than in controls; however, there was no statistical difference between these groups (p = 0.05). This study had fewer patients (24) compared to other studies that measured TNF-α levels in synovial fluid. The sample size of the patients may have influenced the results. Additionally, this study included cases with acute and chronic pain; however, there was no statistically significant difference in TNF-α levels between these groups.
Takahashi et al. 15 did not detect any difference in TNF-α levels between patients and healthy subjects. In this study, the patients had been treated for three months, which could have reduced inflammation and consequently the levels of interleukins. Medications were suspended at least two weeks prior to the synovial fluid collection; however, the treatment may have already helped to control the inflammation. In addition, patients were using an occlusal splint and undergoing physiotherapy, which can also decrease inflammation. There is a possibility that these treatments could have influenced the results.
Furthermore, the control group only comprised men.
Campello CP, Lima ELS, Fernandes RSM, Porto M, Muniz MTC -TNF-α levels and presence of SNP-308G/A of TNF-α gene in temporomandibular disorder patients 13 A recent study in transgenic mice observed that high concentrations of TNF-α cause catabolic changes that considerably affect the TMJ, causing irregular bone erosion and loss of cartilage. 25 The SNP -308G/A in the promoter region 13 is associated with higher levels of TNF-α. 24 The A allele and AA genotype of the SNP -308G/A are associated with an increase in TNF-α production. 13,24 Five studies described in this review Further research is required not only to measure TNF-α concentrations and identify the -308G/A TNF-α polymorphism, but also to detect other interleukins and polymorphisms that could be inflammatory markers in TMD cases. It is essential to detect TMD risk factors that can predispose subjects to develop TMD or aggravate this disorder. It is necessary to develop a more specific treatment to reduce or eliminate pain and promote a better quality of life for these patients.
It is also important to conduct tests that assess the psychological status and somatosensory profiles of TMD patients, because these assessments can show different effects in patients' pain profile; consequently, they could contribute to understanding the pain mechanism, its maintenance, and treatment guidelines. 23 An investigation demonstrated that centrally mediated myalgia and TMD with disc displacement had higher pain intensity than masticatory myofascial pain, local myalgia, capsulitis/synovitis, and continuous neuropathic pain, which could be explained by genetic, psychological, social, or behavioral aspects. 30 Elevated levels of TNF-α and its -308G/A polymorphism, which is associated with higher concentrations of this interleukin, 13,24 could be present in patients with greater pain intensity.
The limitations of the studies analyzed in this review were the small sample sizes considered in some studies, different diagnostic criteria, and the fact that while some studies involved both women and men, some control groups consisted only of men. It is essential to follow the same diagnostic criteria, taxonomy, and nomenclature, because research questions and findings can be standardized; consequently, clinicians can better diagnose and monitor their patients. 5 Few studies have evaluated the TNF-α profile in patients with TMD. Our suggestion for similar studies in future is to work with larger sample sizes that have also women constituting the control group, because TMD is more severe in women. 3 In addition, these studies analyzed interleukin levels in different fluid samples, like synovial fluid and blood, which makes it difficult to compare the articles. We suggest that TNF-α levels and the analyzed polymorphism can be used as inflammatory markers for developing a more targeted treatment protocol.

CONCLUSION
Most TMD patients showed a predisposition to a greater pro- Overall responsibility:

MTCM.
The authors report no commercial, proprietary or financial interest in the products or companies described in this article.