Temporomandibular Disorders and Serological Tests in Patients with Rheumatoid Arthritis

Abstract

Background: Rheumatoid Arthritis (RA) is a systemic and chronic autoimmune disease with inflammation at the synovial joints. The purposes of this study were to evaluate the correlation between serological variables and temporomandibular disorders (TMDs) in patients diagnosed with RA, evaluated through diagnostic criteria for temporomandibular disorders (DC/TMD), and to check the influence of comorbidities on the different TMD signs and symptoms, or any serological variables. Methods: This observational cohort research study included seventeen patients affected by RA. The comorbidities and some variables from the initial serological analyses were collected from the clinical rheumatological charts. Then, the presence of any of the following TMD signs/symptoms, temporal myalgia, temporomandibular joint arthralgia, click or crepitus, was evaluated through the symptom questionnaire of the DC/TMD during clinical evaluation following the DC/TMD examination form. Results: Rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA), and anti-nuclear antibody (ANA) positivity were present in 82.4%, 52.9%, and 41.2% of patients, respectively. Indicators of tissue inflammation were evaluated with median values of 21 mm/h for erythrocyte sedimentation rate (ESR) and 0.50 mg/dL for C-reactive protein (CRP). The RA patients presented comorbidities such as hypertension in 70.6% and diabetes in 23.5%. Negative ACPA had a significant association with myalgia (p = 0.03), and positive ANA was significantly associated with crepitus (p = 0.05). Conclusion: ANA and ACPA evaluation can be considered predictive serological tests associated with specific TMDs. Conversely, no influence of any comorbidities was found between different TMD signs and symptoms, or any serological variables.

1. Introduction

Rheumatoid Arthritis (RA) is a systemic and chronic autoimmune disease with persistent inflammation at the synovial joints causing morphological deformities and pain. It is one of the most common autoimmune diseases, affecting 1–1.5% of the population worldwide with a higher incidence in females. The onset can occur at any age, but peaks between 30 and 50 years [1,2,3,4,5,6]. The most important epidemiological study in Italy was conducted on almost five million Italian people aged ≥18 years. In the Italian population, Rossini et al. found an RA prevalence and incidence of 0.41% and 35/100,000, respectively, without apparent differences between northern and southern regions or urban and rural areas [7].

The etiopathogenesis is quite unknown, and is influenced by both genetic and environmental factors [8,9,10,11]. Specifically, it is largely accepted that several factors are involved in a genetically predisposed substrate. Different studies state that heritability is around 65% [7]. Genes inside the HLA locus, especially HLA-DRB1, represent just under half of the genetic component of susceptibility, as well as being associated with greater disease severity. From a gender viewpoint, females are two to three times more likely to acquire RA than males. It has been hypothesized that this is partially caused by the stimulatory effects of estrogen on the immune system. There are conflicting opinions in the literature regarding pregnancy and the risk of developing RA, although in general a trend towards a protective effect has been demonstrated [3]. Among the risk factors implicated in the development of RA are smoking, obesity, and periodontal disease; the gut microbiome and infections were also involved. Smoking represents an important risk due to the presence of anti-citrullinated protein antibodies (ACPA), which are fundamental diagnostic and prognostic markers in RA; the risk is further increased in the occurrence of specific HLA-DRB1 alleles. This depends mainly on the immunomodulatory effects of smoking, comprising a decrease in the phagocytic and antibacterial functions of alveolar macrophages, changes in cytokine production, and oxidative stress.

Aside from its effect on susceptibility, cigarette smoking can also be considered a risk factor for a greater severity of the disease. While the etiological factors are conflicting, large epidemiological studies state that obesity may be related to a modest spread in the risk of developing RA. Additional studies have shown that obesity is usually associated with worse subjective measures of disease activity, which may be mystified by osteoarthritis, disability, and chronic pain [3].

Autoimmunity and general systemic and joint inflammatory burden drive the destructive development of the disease [1]. According to several authors, the alterations associated with the pathology may derive from chronic inflammation and an autoimmune reaction caused by an external or endogenous pathogen acting on a genetic substratum. The pathogenesis concerns synovial proliferation over the surface of the cartilage, producing a tumor-like mass (pannus) that destroys the articular cartilage and the adjacent bone tissue, causing inflammation that affects the peripheral joints, in particular diarthrosis, often symmetrically [9]. The disease is polyarticular, and most commonly affects the hands, feet, wrists, elbows, shoulders, cervical spine, and knees. The lumbar spine is spared. Extra-articular manifestations (EAMs) may involve the eyes, lungs, heart, nervous system, kidneys, and blood vessels [12]. The EAMs of RA may appear at any time after disease onset, and the presence of these signs is related to amplified mortality. Particularly, multi-organ involvement in RA is more common in patients with severe, active disease and those with positive rheumatoid factor (RF)/anti-CCP Abs and/or positive HLA-DR4. EAMs include the involvement of the skin, eyes, heart, lungs, renal, nervous, and gastrointestinal systems, with tendons, ligaments, and fascia. Consequently, it is essential to recognize EAM because the management is frequently aimed at controlling the underlying RA disease [2].

Among the most frequent manifestations are keratoconjunctivitis, the inflammation of the cornea and conjunctiva, which manifests itself as burning, itchy eyes, pressure behind the eye, or a feeling of grittiness in the eye. Among the less frequent but more destructive processes is scleritis, which is characterized by a very painful inflammation of the sclera. Pleuro-pulmonary involvement is common in RA, and pleural effusions may be found on routine chest X-rays.

Patients with pleural effusions may not have symptoms and may not need any therapy, as effusions usually resolve spontaneously or with the management of the joint disease.

Lung nodules also may be reported in patients with RA. They usually appear in patients with long-standing RA pathology and patients with concomitant subcutaneous rheumatoid nodules. The prognosis of rheumatoid pulmonary nodules is commonly good, but monitoring for potential neoplasms is necessary, especially in those subjects who have a history of smoking [1,2,3]. Male patients, subjects who are older at the onset of the disease, and those with more severe disease show a greater risk of developing ILD.

Considering the systemic inflammatory nature of RA, the main cardiac manifestation in these patients is atherosclerosis. Several studies have found increased cardiovascular morbidity in patients with RA; compared to age- and sex-matched controls, patients with RA present an increased risk of cardiovascular death, ischemic heart disease, and heart failure. Osteoporosis in RA occurs from an interaction of factors, comprising systemic and local inflammation, patient immobilization caused by joint damage and pain, and the associated treatment with glucocorticoids.

Hematologic anomalies are usual in RA, and bone marrow suppression may result from both pathological processes and drug therapy. Clinically, this may present as anemia, leukopenia, neutropenia, eosinophilia, thrombocytopenia, or thrombocytosis. Anemia of long-term disease is the most frequent anomaly, which may present concurrently with iron deficiency anemia and will tend to improve with good disease control. Mononeuritis multiplex is an asymmetric sensory and/or motor peripheral neuropathy that destroys at least two separate, apparently random, nerve areas. Mononeuritis multiplex is usual in diabetes but may also be seen in vasculitis, like RA [2].

Regarding the diagnostic criteria, there are three key factors indicating probable RA according to the more updated classification (ACR/EULAR 2010 Classification) [13]: symmetrical arthritis of small joints (swelling and morning joint stiffness), symptoms lasting longer than 6 weeks, elevated concentrations of C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) (when its titer is three times increased), or anti-nuclear antibody (ANA) [6,14,15,16,17,18].

However, currently, there are no single pathognomonic laboratory or imaging findings that definitively diagnose this disease [19]. Although structural changes, which can be visualized by conventional X-rays or other imaging techniques, best distinguish RA from other arthritic disorders, joint damage is rarely apparent in the very early stages of disease, but rather accumulates consistently over time [1]. Therefore, RA diagnosis is also, and above all, clinical, based on the pattern of the following physical symptoms, i.e., swollen joints, redness at affected joints, joint stiffness in the morning, low-grade fever, fatigue, and loss of appetite [19].

The early diagnosis and treatment of RA have extensively shown a strong potential for the improvement of disease outcomes. Established evidence supports the impact of early interventions in terms of early disease activity control, leading to a lower rate of radiographic progression and development of disability. Early diagnosis and treatment are associated with better outcomes in terms of survival, which is mainly dependent on the early suppression of disease activity and prevention of functional impairment. Therefore, the model of care, including early diagnosis, is consistently regarded as a standard of care according to current international RA guidelines. Some recent research showed that quality of care in the population is suboptimal, even in efficient healthcare systems, due to delays in referral and diagnosis [20]. It has been recognized that early therapeutic intervention improves clinical outcomes and reduces the increase in joint damage and disability. Certainly, treating patients at a stage at which the evolution of joint destruction can still be prevented would be ideal [1].

The joints are primarily involved but there are other extra-articular manifestations, such as rheumatoid nodules, pulmonary involvement or vasculitis, and systemic comorbidities [8,9,10,11]. Specifically, RA may severely affect the normal functions of temporomandibular joints (TMJs) in a wide range of the population, reported to be from 4.7% to 88% of adults [6]. The involvement of the TMJ follows the same destructive path occurring in other joints, directly correlated with the severity and duration of the RA. In the initial phase, there may be synovial hyperemia, lymphocyte infiltration, fibrinoid degeneration, and granulation tissue until joint degeneration. From that point on, there may be the formation of scarring and fibrous adhesion [21]. The disease may lead to severe TMJ disabilities including arthralgia, limited mandibular movements with related functions, difficulty in eating, morning stiffness during mouth opening upon waking, weakness of the masticatory muscles with decreased bite force, and joint noises [21].

TMJ radiographic records may only show abnormalities in the integrity of the bone cortex, bone erosions, asymmetry and flattening of the condyles, and joint space narrowing. Moreover, these TMJ signs and symptoms are often underestimated or, worse, ignored, so the diagnosis of TMJ involvement comes too late to prevent permanent damage. The monitoring of this joint should be considered to prevent irreversible issues [22,23].

As abovementioned, RF and ACPA are common, reliable, and regularly used methods of RA assessment [6,14,15,16,17,18]. If these indices correlate with temporomandibular disorders (TMDs) [24,25,26,27] in RA patients, then they can be used as potential predictors of TMJ affection in RA patients.

In the literature, only two clinical trials evaluated the TMD prevalence and the serological tests in RA patients [6,28]. The ACPA showed a significant correlation with the development of clinical TMDs. There is still no evidence of the presence of a direct association between serological tests and TMDs.

The primary objectives of this study were to evaluate, in patients diagnosed with RA, the possible correlation between serological variables and the main TMD signs and symptoms evaluated through the diagnostic criteria for temporomandibular disorders (DC/TMD). The secondary objective was to check the possible influence of any comorbidities with the different TMD signs and symptoms, or any serological variables.

2. Materials and Methods

The research was conducted in accordance with the revised Helsinki Declaration, and it was approved by the Ethics Board Committee of the University of Campania Luigi Vanvitelli, Italy (Prot N° 309), before starting the data collection. All subjects had signed informed consent for the use of personal information in the study.

This prospective observational cohort study was conducted on consecutive patients referred by the Rheumatological Unit to the Orthodontic Program of the University of Campania Luigi Vanvitelli, in Naples, Italy, from January 2019 to December 2022. The inclusion criteria were (1) age higher than 25 years old; (2) a confirmed diagnosis of RA according to the 2010 ACR/EULAR criteria [14]; (3) regular follow-up by a rheumatologist; and (4) complete serological and clinical records. Patients were excluded if they had incomplete medical records, congenital or acquired facial anomalies, a history of facial fractures, previous maxillofacial surgery, or previous orthodontic treatment during the permanent dentition, i.e., previous treatment with occlusal splints for treating TMDs.

Starting from a total of 28 selected subjects, 8 were excluded for missing data, and 3 were discarded for previous treatment with splints. Thus, a total of 17 patients were included in the final analysis after the collection of the previous primary data reported in the clinical charts.

Information on the variables from the serological analyses and the comorbidities of the RA were collected by the rheumatologists and reported in the clinical charts during the initial consultations, as secondary data. Specifically, the ESR (mm/h, and +/−), C-reactive protein (mg/dL, and +/−), RF (+/−), ACPA (+/−), and ANA (+/−) were evaluated.

More in detail, the ESR normal values are 0–15 mm/h in men and 0–20 mm/h in women; therefore, the values outside these ranges were considered positive. For the C-reactive protein parameter, its value is considered positive when exceeding 1 mg/dL. RF are autoantibodies that bind to epitopes within the constant region (Fc) of immunoglobulin type G (IgG). Different assays are used to detect RF. Hemagglutination tests are currently considered to be obsolete and have been replaced by more or less automated immunoassays. [29] Regarding ACPA detection, different generations of tests are currently available. Initially, ACPA was detected by ELISA using citrullinated recombinant rat filaggrin. Subsequently, the sensitivity of ACPA tests was enhanced without compromising specificity by using synthetic cyclic citrullinated peptides (CCP), most commonly version 2 (CCP2) [22]. In Europe, the anti-CCP2 test is the most commonly used test, manufactured and distributed by different companies and assay formats [29].

The presence of any of the main TMD signs and symptoms, specifically, myalgia in the temporal area, TMJ arthralgia, click, or crepitus, was evaluated through the validated Italian version of the DC/TMD [https://ubwp.buffalo.edu/rdc-tmdinternational/tmd-assessmentdiagnosis/dc-tmd-translations/ (accessed on October 2023) during the subsequent clinical evaluations performed in the Unit of Orthodontics by specialists in orthodontics and orofacial pain.

In particular, records about the abovementioned TMJ signs and symptoms were derived from the “Symptom Questionnaire” of the updated DC/TMD examination forms [27], focusing on the assessment of referred pain, headache, joint noises, and eventual previous locking of the jaws (Figure 1).

All data were shared in an online Excel sheet between the specialists of the two Units in order to check the eventual unavailable information in every patient.

Other information on historical and family anamnesis was excluded, being unrelated to the purposes of this research study.

Statistical Methods

Continuous variables were reported as either the means and standard deviation or median and interquartile ranges (IQRs) according to their distribution, as assessed by the Shapiro–Wilk normality test. Categorical variables were reported as absolute frequencies and percentages. Differences in baseline characteristics of patients affected and unaffected were tested using a Student’s t-test or Wilcoxon test (according to their distribution) for continuous and a Pearson chi-squared test or Fisher’s exact test for categorical variables. Moreover, the group differences analyses were performed to estimate the effect of serological variables on the temporomandibular disorders (absence/presence). All the statistical tests with p-values equal to or smaller than 0.05 were considered statistically significant. The analyses were conducted using the R statistical package (version 3.5.3, R Core Team, Foundation for Statistical Computing, Vienna, Austria).

3. Results

The study included 17 patients (15 females and 2 males) with RA, with a median age of 48 years. RF, ACPA, and ANA positivity were present in 82.4%, 52.9%, and 41.2% of patients, respectively. Indicators of tissue inflammation were evaluated with median values of 21 mm/h for ESR and 0.50 mg/dL for CRP.

The RA patients presented comorbidities such as hypertension in 70.6%, diabetes in 23.5%, lung disease in 7.6%, and atherosclerosis in 11.8%; only one patient showed, in addition, hepatic steatosis and hyperuricemia (

Table 1. Descriptive statistics on variables included in the research.

Characteristic	N = 17 1
Gender
Female	15.0 (88.2%)
Male	2.0 (11.8%)
Age	48.00 (16.00)
Hypertension	12.0 (70.6%)
Diabetes	4.0 (23.5%)
Hepatic Steatosis	1.0 (5.9%)
Hyperuricemia	1.0 (5.9%)
Lung Disease	3.0 (17.6%)
Atherosclerosis	2.0 (11.8%)
ESR	21.00 (22.00)
CRP	0.50 (1.04)
RF
Negative	3.0 (17.6%)
Positive	14.0 (82.4%)
ACPA
Negative	8.0 (47.1%)
Positive	9.0 (52.9%)
ANA
Negative	10.0 (58.8%)
Positive	7.0 (41.2%)

n (%); Median (IQR). ¹ Median (IQR).

).

As seen in

Table 2. Association between possible predictor variables and myalgia.

	Myalgia
Characteristic	No, N = 5 1	Yes, N = 12 1	p-Value 2
Gender			0.51
Female	4.0 (80.0%)	11.0 (91.7%)
Male	1.0 (20.0%)	1.0 (8.3%)
Age	54.00 (19.00)	47.00 (12.25)	0.96
Hypertension	3.0 (60.0%)	9.0 (75.0%)	0.60
Diabetes	0.0 (0.0%)	4.0 (33.3%)	0.26
Hepatic Steatosis	0.0 (0.0%)	1.0 (8.3%)	0.99
Hyperuricemia	0.0 (0.0%)	1.0 (8.3%)	0.99
Lung Disease	2.0 (40.0%)	1.0 (8.3%)	0.19
Atherosclerosis	1.0 (20.0%)	1.0 (8.3%)	0.51
ESR	5.00 (28.00)	23.00 (15.00)	0.37
CRP	1.00 (1.98)	0.40 (1.00)	0.87
RF			0.51
Negative	0.0 (0.0%)	3.0 (25.0%)
Positive	5.0 (100.0%)	9.0 (75.0%)
ACPA			0.03
Negative	0.0 (0.0%)	8.0 (66.7%)
Positive	5.0 (100.0%)	4.0 (33.3%)
ANA			0.34
Negative	4.0 (80.0%)	6.0 (50.0%)
Positive	1.0 (20.0%)	6.0 (50.0%)

¹ Median (IQR) or Frequency (%). ² Fisher’s exact test; Wilcoxon rank-sum test.

, negative ACPA had a significant association with myalgia (p = 0.03). No other statistical significance was found between myalgia and the other variables. Moreover, 12 patients reported myalgia (females 91.7% and males 8.3%). Among these patients, the ESR median value was 23 mm/h, while RF positivity was present in 75% of patients.

Some of the possible predictor variables and TMJ outcomes, specifically arthralgia and click, showed no significant association. The arthralgia was referred by 90.9% of females and 9.1% of males. The median ESR value was 21 mm/h, while the CRP median value was 0.50 mg/dL in patients who reported arthralgia (

Table 3. Association between possible predictor variables and arthralgia.

	Arthralgia
Characteristic	No, N = 6 1	Yes, N = 11 1	p-Value 2
Gender			0.99
Female	5.0 (83.3%)	10.0 (90.9%)
Male	1.0 (16.7%)	1.0 (9.1%)
Age	53.50 (14.50)	46.00 (13.50)	0.76
Hypertension	3.0 (50.0%)	9.0 (81.8%)	0.28
Diabetes	0.0 (0.0%)	4.0 (36.4%)	0.24
Hepatic Steatosis	0.0 (0.0%)	1.0 (9.1%)	0.99
Hyperuricemia	0.0 (0.0%)	1.0 (9.1%)	0.99
Lung Disease	2.0 (33.3%)	1.0 (9.1%)	0.51
Atherosclerosis	1.0 (16.7%)	1.0 (9.1%)	0.99
ESR	25.50 (37.00)	21.00 (15.50)	0.76
CRP	0.61 (0.96)	0.50 (1.52)	0.48
RF			0.99
Negative	1.0 (16.7%)	2.0 (18.2%)
Positive	5.0 (83.3%)	9.0 (81.8%)
ACPA			0.13
Negative	1.0 (16.7%)	7.0 (63.6%)
Positive	5.0 (83.3%)	4.0 (36.4%)
ANA			0.99
Negative	4.0 (66.7%)	6.0 (54.5%)
Positive	2.0 (33.3%)	5.0 (45.5%)

¹ Median (IQR) or Frequency (%). ² Fisher’s exact test; Wilcoxon rank-sum test.

).

The click was observed in eight patients (87.7% females and 12.5% male). Patients with no click presented median values of ESR and CRP of about 19 mm/h and 1 mg/dL, respectively. Furthermore, seven patients with no click and seven patients with click were RF-positive (

Table 4. Association between possible predictor variables and click.

	Click
Characteristic	No, N = 9 1	Yes, N = 8 1	p-Value 2
Gender			0.99
Female	8.0 (88.9%)	7.0 (87.5%)
Male	1.0 (11.1%)	1.0 (12.5%)
Age	46.00 (12.00)	56.00 (17.50)	0.16
Hypertension	6.0 (66.7%)	6.0 (75.0%)	0.99
Diabetes	4.0 (44.4%)	0.0 (0.0%)	0.08
Hepatic Steatosis	1.0 (11.1%)	0.0 (0.0%)	0.99
Hyperuricemia	1.0 (11.1%)	0.0 (0.0%)	0.99
Lung Disease	1.0 (11.1%)	2.0 (25.0%)	0.58
Atherosclerosis	0.0 (0.0%)	2.0 (25.0%)	0.21
ESR	19.00 (30.00)	25.00 (19.50)	0.99
CRP	1.00 (1.04)	0.36 (1.24)	0.63
RF			0.99
Negative	2.0 (22.2%)	1.0 (12.5%)
Positive	7.0 (77.8%)	7.0 (87.5%)
ACPA			0.64
Negative	5.0 (55.6%)	3.0 (37.5%)
Positive	4.0 (44.4%)	5.0 (62.5%)
ANA			0.99
Negative	5.0 (55.6%)	5.0 (62.5%)
Positive	4.0 (44.4%)	3.0 (37.5%)

¹ Median (IQR) or Frequency (%). ² Fisher’s exact test; Wilcoxon rank-sum test.

).

In

Table 5. Association between possible predictor variables and crepitus.

	Crepitus
Characteristic	No, N = 14 1	Yes, N = 3 1	p-Value 2
Gender			0.99
Female	12.0 (85.7%)	3.0 (100.0%)
Male	2.0 (14.3%)	0.0 (0.0%)
Age	53.00 (16.75)	42.00 (6.00)	0.15
Hypertension	10.0 (71.4%)	2.0 (66.7%)	0.99
Diabetes	3.0 (21.4%)	1.0 (33.3%)	0.99
Hepatic Steatosis	0.0 (0.0%)	1.0 (33.3%)	0.18
Hyperuricemia	1.0 (7.1%)	0.0 (0.0%)	0.99
Lung Disease	3.0 (21.4%)	0.0 (0.0%)	0.99
Atherosclerosis	2.0 (14.3%)	0.0 (0.0%)	0.99
ESR	22.00 (20.50)	21.00 (22.00)	0.85
CRP	0.40 (0.95)	4.00 (2.70)	0.23
RF			0.99
Negative	3.0 (21.4%)	0.0 (0.0%)
Positive	11.0 (78.6%)	3.0 (100.0%)
ACPA			0.99
Negative	7.0 (50.0%)	1.0 (33.3%)
Positive	7.0 (50.0%)	2.0 (66.7%)
ANA			0.05
Negative	10.0 (71.4%)	0.0 (0.0%)
Positive	4.0 (28.6%)	3.0 (100.0%)

¹ Median (IQR) or Frequency (%). ² Fisher’s exact test; Wilcoxon rank-sum test.

, it can be seen that only three RA patients presented a crepitus, but they were all RF-positive. The statistical significance was demonstrated between crepitus and ANA positivity (p = 0.05). Both ACPA and ANA were related to clinical TMDs (myalgia and crepitus). Negative ACPA had a significant association with myalgia (p = 0.03), and positive ANA was significantly associated with crepitus (p = 0.05).

4. Discussion

The percentage of women affected by RA in the study sample was higher than males (about 88% vs. 11%), and this is in agreement with the worldwide female gender prevalence of rheumatological conditions reported in the recent literature [28,29,30].

The relationship between different serological factors and TMJ involvement in adults affected by RA has already been demonstrated in previous publications [6,28]. Specifically, authors evaluated the association of some serological tests with the prevalence of TMJ disorders assessed by the first research diagnostic criteria (RDC)/TMD axes [28] and with the radiographic TMJ changes. Youssef et al. [6] showed that on CBCT evaluations, the ACPA can be a good indicator of changes in condylar measurements, mainly in the case of highly destructive disease of the TMJ. Conversely, RF level was considered a poor predictor of condylar size or osteoarthritic changes in RA patients. Recent research showed that RA patients, mainly females, follow an individual skeletal growth pattern evaluated using bidimensional radiological examinations, which are not affected by inflammatory parameters, even if they show joint anatomical asymmetry [31,32].

Regarding the serological parameters, Van Hoovel et al. stated that there is some evidence that specificity in RA classification can be improved by refining the serological weight scoring, taking into account the nature of the antibody (RF versus ACPA), their levels, and the occurrence of combined RF/ACPA positivity. There is now increasing awareness that efforts should be undertaken to harmonize the interpretation of RF and ACPA test results in order to further improve the classifications and diagnosis of RA [29].

The current research evaluated, for the first time in patients affected by the RA systemic disease, the presence of signs and symptoms of TMDs, assessed through the updated DC/TMD, [24] and the putative correlation with some of the RA diagnostic factors revealed by the following serological tests: ESR, CRP, RF, ACPA, and ANA.

The assessment of the DC/TMD in this study was carried out by only one examiner to avoid any performance bias. A statistically significant association was found between a negative ACPA and the presence of pain related to the masticatory muscles. This outcome was similar to the previous research in which 80% of TMDs were described as pain in the orofacial region. Similarly, Mortazavi et al. showed a significant correlation between the clinically evaluated presence of TMDs in RA patients and the CRP (57.69%), ACPA (94.23%), and RF (86.53%) serological levels [28].

Moreover, in our study, RF has been found to be positive in more than 80% of patients with RA. The comorbidities more correlated with RA in our sample were hypertension (70%), and also diabetes (23.5%). However, there is no evidence of the possible correlation of any comorbidities with either TMDs or serological tests; thus, no prediction can be made about this point.

In conclusion, ACPA and RF were confirmed to be related to clinical TMDs, and this is important evidence for clinicians within the multidisciplinary diagnostic path in patients affected with RA. Specifically, myalgia is correlated with ACPA negativity, and this parameter should be disseminated among rheumatologists in order to refer RA patients with these characteristics to an orofacial pain specialist for the possible early diagnosis and management of TMD. In this regard, it is important to underline the results of recent research on the cranial structure and condylar asymmetry checked on panoramic X-rays. In patients with RA, compared to a healthy adult control group, the condyles showed a bilateral asymmetry in RA patients due to the high turnover of this joint reacting to severe systemic inflammation [33]. So, it is pivotal to diagnose TMJ early and monitor it in conditions of arthritis, not only assessing the signs and symptoms revealed by patients but also evaluating predictors through additional serological and instrumental exams.

The strength of this research protocol is that we have found some predictive factors for TMDs in patients affected by RA using the updated DC/TMD.

A limitation is the small sample size which consisted of consecutive patients diagnosed with RA in a single university hospital over a specific range of years. However, this should just be the beginning of a future multicentric study that will include several centers using a similar methodology of research.

Thus, future studies are ongoing to validate the serological variables with the presence of myalgia and crepitus involving a wider sample size of patients affected by RA, comparing them with a similar control group.

5. Conclusions

In patients diagnosed with RA, a significant correlation between TMD symptoms was evaluated through DC/TMD. Specifically, myalgia of the masticatory muscles is related to ACPA negativity, whereas the presence of crepitus is correlated with ANA positivity. Thus, within the limitations of the study, ANA and ACPA evaluation can be considered as predictive serological tests associated with specific TMJ disorders. Conversely, no influence of any comorbidities was found between different TMD signs and symptoms, or any serological variables.