Temporomandibular Internal Derangements Denote Activity of Axial Spondyloarthritis

Abstract

Objectives

The group of spondyloarthritis (SpA) disorders shares common clinical manifestations, including internal derangement (ID) of temporomandibular joint (TMJ). This study aimed to investigate SpA activity in patients with ID of TMJ.

Materials and Methods

We assessed 200 patients with neck pain using the Assessment of Spondyloarthritis International Society (ASAS) criteria. TMJ was examined using Diagnostic Criteria for Temporomandibular Disorders (DC/TMD protocol). Patients with SpA were divided into three groups: symptomatic ID of TMJ, asymptomatic ID of TMJ, or healthy TMJ (controls). Activity of SpA was evaluated using the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Disease Activity Index in Psoriatic Arthritis (DAPSA), patients' self-estimated SpA activity, difficulties in performing daily activities, pain intensity (visual analogue scale) and laboratory parameters.

Results

Patients with symptomatic and asymptomatic ID showed statistically significantly increased ASDAS, anti-streptolysin titer, patients' self-estimated axial pain and activity of SpA, and decreased hematocrit than the control. Patients with symptomatic ID also had statistically significant earlier onset of SpA, along with increased BASDAI and DAPSA, total body pain, difficulties in performing daily activities, platelet count, and serum alpha-amylase but lower hemoglobin concentration than controls. Patients with asymptomatic ID had higher frequencies of exacerbated axial SpA and sacroiliac joint ankylosis compared to the control.

Conclusion

All patients with SpA and ID showed increased axial disease activity.

Introduction

Spondyloarthritis (SpA) encompasses a group of related immune disorders with similar etiopathogenetic mechanisms and clinical manifestations (1), including HLA-B27+ SpA, reactive arthritis, psoriatic arthritis, enteropathic SpA associated with intestinal inflammation, and undifferentiated SpA (2). A genetic predisposition, notably the expression of HLA-B8, B27, B38, and B39 genes, explains the onset of the disease in young adults (3), as verified by magnetic resonance imaging (MRI) and classified as non-radiological axial (nr-ax) SpA (4). All the above-mentioned forms of SpA can manifest as temporomandibular disorders (TMDs), which have recently been recognized as more than localized inflammation or disorders, instead representing a pathological process underlying the axial form of SpA (5). Untreated nr-axSpA can lead to structural changes in the spine, detectable through radiography and represent radiographic axial (r-ax) SpA or ankylosing spondylitis (4). Radiographic axSpA is characterised by erosion, fat metaplasia, and ankylosis of the sacroiliac joints and/or spine (6). Not all nr-axSpA cases progress to r-axSpA, with progression likely dependent on the severity of damage (4). Pain in the spine or peripheral joints in the peripheral form of the disease is the primary symptom that prompts patients with SpA to consult a rheumatologist and is evaluated at every examination. Axial SpA usually starts as inflammatory low back pain and gradually spreads up the spine (4). Thus, patients with axial SpA often report varying intensities of neck pain radiating to the shoulders and head, including orofacial pain (7). They may also report difficulties with neck movements associated with difficulties in opening or closing the mouth, pain, stiffness, clicking and/or crepitus in the temporomandibular joints (TMJs), and sensitivity of the masticatory muscles (8).

Currently, the relationship between TMDs and SpA is not entirely understood. The most frequent TMDs can be grouped as (I) disorders related to muscle and joint pain and headaches, and (II) intracapsular disorders related to changes in the position of the intra-articular disc and degenerative changes (9). The intracapsular disorder is also called internal derangement (ID) of the temporomandibular joint (TMJ), and cause chronic pain, clicking or crepitations, respectively (9-11). The disorders related to muscle and joint pain and headaches can coexist with ID (9, 12). The ID of TMJ has a multifactorial origin, involving a combination of biological and mechanical factors (12-14), psychological and social factors (15, 16), and synovitis (17). These factors contribute variably to the pathogenesis of TMDs, collectively causing orofacial pain, masticatory dysfunction, and communication disorders (11, 15). Despite the potential for symptomatic reactive infectious arthritis of the TMJs (18), ID was previously regarded primarily as non-inflammatory disc dysfunction, even in symptomatic subjects (19). Recently, sterile synovitis emerged as one of the significant causes of pain in axial SpA (20-22), including the pain in the TMJ (23-25). Whether the ID of TMJ represents SpA activity remains unknown. Therefore, patients with SpA exhibiting clinically pronounced disturbances of the cervical spine represent a suitable group for the study of symptomatic and asymptomatic IDs. In this investigation, we analysed the activity of SpA in symptomatic and asymptomatic IDs and compared these findings with those from patients with healthy TMJs.

Material and Methods

Patients

The Ethics Committee of the Special Hospital "Thalassotherapia-Opatija," Opatija, Croatia, approved this research (approval number 01-000-00-17/2-2021) on February 10, 2021. Patients with axial and/or peripheral SpA were recruited from the Rheumatology Department of the Special Hospital for Medical Rehabilitation of Heart, Lung, and Rheumatism, "Thalassotherapia-Opatija," Opatija, Croatia, between February 10, 2021 and February 28, 2023, after a clinical rheumatological examination and an examination of their laboratory findings. The inclusion criteria were pain in the cervical spine and age between 18 and 80 years. The exclusion criteria were: rheumatoid arthritis, systemic connective tissue diseases, immunodeficiency, acute infection, pregnancy, malignancy within the last 5 years, uncontrolled diabetes (plasma glucose > 11 mmol/L), uncontrolled arterial hypertension (> 160/100 mmHg), acute coronary events, grade III and IV heart failure according to the New York Heart Association, grade IV and V renal failure, liver lesions (ALT, AST, and GGT three or more times the upper limit of normal), to avoid a significant change in the immune system other than SpA. Patients with congenital/developmental disorders of the TMJs were also excluded. Based on these criteria, 233 patients with SpA were recruited. They provided informed consent for participation, and were referred to a dental medicine specialist for clinical examination of the TMJs. This study adhered to all applicable guidelines aimed at ensuring the proper conduct and safety of participants, including the Helsinki Declaration of the World Medical Association (Edinburgh, 2000). During this study, patients did not change their regular therapy or take additional substances/drugs (placebo).

Rheumatological examination

A rheumatologist examined the patients and diagnosed SpA according to The Assessment of SpondyloArthritis International Society (ASAS) classification criteria (26). The following data were recorded: age (years), sex, body mass index (BMI, kg/m²), duration of SpA, age at onset of SpA (years), and current therapy according to the electronic hospital information system (WinBis, IN2 Ltd., Zagreb, Croatia). Current SpA activity was assessed using the Ankylosing Spondylitis Disease Activity Score (ASDAS), patients’ self-estimated axial and peripheral pain intensity, SpA activity (visual analogue scale [VAS] from 1 to 10) (27), and total body pain (visual analogue scale from 1 to 100 mm). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to assess neck pain (28). The Disease Activity Index for Psoriatic Arthritis (DAPSA) (29) was calculated. We also recorded the patient’s difficulties in performing daily activities (VAS 1-10).

Laboratory analyses

Laboratory analyses were performed using a single 12 mL peripheral venous blood sample obtained from the cubital vein. Erythrocyte, leukocyte, and platelet cell counts, as well as hematocrit and hemoglobin concentrations, were analyzed using a hematology analyzer (Sysmex XN-550, Kobe, Japan). C-reactive protein, serum alpha-amylase, and anti-streptolysin O titer (ASTO) were measured using an automatic biochemical analyzer (Cobas Pro, Roche Diagnostics, and Boehringer Mannheim).

Imaging methods

Patients underwent MRI of the sacroiliac joints and thoracolumbar transition zone, according to the clinical presentation of the disease (Siemens Avanto 1.5 T Syngo MR B17, Erlanger, Germany). MRI was performed without a radiographic contrast agent, following the ASAS protocol (26). Ultrasound (ultrasonic device and linear probe of 20 kHz, Loggic e, General Electric, Niskayuna, New York, USA), X-ray [tube (Siemens, Wuxi, China), table (Siemens, Munich, Germany)] or MRI (Siemens Avanto 1.5 T Syngo MR B17) were used to assess the peripheral form of SpA.

Examination of temporomandibular joints (TMJs)

Clinical examination of the TMJs was performed by a dentist according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD protocol) (9). The results were recorded in the DC/TMD form and analyzed (30). Axis I is a form for clinical examination, and Axis II consists of a series of self-administrated instruments that assess functional, behavioral and psychosocial status. The diagnosis was established by integrating the findings from Axis I and Axis II, following the diagnostic algorithms for "Pain associated with TMJ and headache" and "Joint disorders and degenerative joint disorders" (31).

Statistical analyses

Statistical analyses were performed using Statistica 14.0.0.15 (TIBCO, Software Inc., Palo Alto, California, USA). All numerical parameters were normally distributed. Differences among three groups for continuous scales were analyzed using one-way analysis of variance (ANOVA). Tukey’s post-hoc test analyzed differences between any two of three researched groups, and Bonferroni correction served to exclude a false positive result. Categorical data were analyzed using Chi-square tests for multiple independent samples with Yates correction, which improved the accuracy of the p-value obtained with Chi-square tests. In the case of a statistically significant difference obtained by the Yates correction between two groups of categorical data, the significance was checked using the Fischer’s exact test, which also precisely determines the P value. Variables on continuous scales were presented as means and 95% of confidence intervals, while categorical variables were presented as counts and percentages.

Results

Allocation of patients in the investigation groups

A flowchart depicting the recruitment and distribution of patients with SpA is provided (Figure 1).

Figure 1.

Recruitment and allocation of patients with spondyloarthritis (SpA) to the assessment groups. Abbreviations: ASAS – The Assessment of Spondyloarthritis International Society; DC/TMD – Diagnostic Criteria for Temporomandibular Disorders; n – number of patients; TMDs – temporomandibular disorders; TMJs – temporomandibular joints.

Following clinical examination of the TMJs in 233 patients with SpA using the DC/TMJ protocol, 33 patients with disorders related to muscle and joint pain and headache without ID were excluded from the study. The remaining 200 patients diagnosed as ReA (n = 62), PsA (n = 57), HLA-B27+ SpA (n = 33), enteropathic SpA (n = 8), and undifferentiated SpA (n = 40) remained in the research. Among these, 114 patients (57% of the 200) were diagnosed with one or more IDs, including disc displacement with reduction (n = 77), disc displacement with reduction and intermittent locking (n = 10), disc displacement without reduction and with limited opening (n = 9), disc displacement without reduction and without limited opening (n = 3), and degenerative joint disease (n = 41). Of these 114 patients with ID, 48 also had concurrent pain associated with TMJ and headache, which included local myalgia (n = 3), myofascial pain (n = 17), myofascial pain with spreading (n = 14), and headache attributed to TMDs (n = 14). Among patients with ID, 64patients (56%) felt pain of articular origin according to the DC/TMD protocol and they were classified as symptomatic ID in this research. Patients with ID of TMJ without articular pain, 50 (44%) were considered asymptomatic regardless of whether they experienced a joint’s sounds. Healthy TMJs were found in 86 patients with SpA (43%), representing the control group. Therefore, 200 patients with SpA were categorized into three groups based on the clinical examination of the TMJs as follows: patients with symptomatic ID (group A), patients with asymptomatic ID (group B), and patients with healthy TMJs (group C or controls).

Radiological findings and therapy of patients with SpA

Table 1 shows radiologic findings and therapies for SpA. Exacerbation of axial SpA was most common in patients with asymptomatic ID of TMJ (74%), significantly higher than in the control group (52.3%; P= 0.0401 Chi-square test; P = 0.0209 Yates-corrected Chi-square test; P = 0.0098, Fisher’s exact test) but not significantly different from those with symptomatic ID. Ankylosis was also more prevalent in patients with asymptomatic ID (24%) compared to 8.13% in the control (P = 0.0319 Chi-square test; P = 0.0206, Yates-corrected Chi-square test; P = 0.0113, Fisher’s exact test). The proportion of patients with peripheral SpA did not differ across the groups, although peripheral SpA was expressed in over 80% of patients, primarily due to enthesitis. Patients in all three research groups received comparable treatments, including non-steroidal anti-inflammatory drugs, sulfasalazine, and methotrexate, or were without therapy at the time of recruitment in the study.

Table 1. Radiological findings in patients with SpA and medical treatment of spondyloarthritis (SpA) 
Differences among groups of patients with symptomatic internal derangement ((ID) of temporomandibular joint (TMJ) (group A), asymptomatic ID of TMJ (group B) and control (group C) were analyzed using tests for comparing multiple independent samples (Chi-square test with Yates correction and Fisher exact one-tailed test). Statistical significance (P) between group A and group C (^a); group B and group C (^b); Yates correction (^y).

Patients with SpA	Group A N/64 (%)	Group B N/50 (%)	Group C N/86 (%)	Chi-square test for multiple independent samples	Chi-square test Yates correction	Fisher’s exact test
Radiological findings in patients with SpA				P levels
Axial type	42 (65.6)	40 (80.0)	54 (62.8)	0.1029
Exacerbation of axial SpA	36 (56.2)	37 (74.0)	45 (52.3)	0.0401	b0.0127; y0.0209	b0.0098
Vertebral corner inflammatory lesion	10 (15.62)	13 (26.0)	11 (12.8)	0.1329
Symmetric BM edema of SIJs	16 (25.0)	10 (20.0)	15 (17.4)	0.5230
Asymmetric BM edema of SIJs	18 (28.12)	24 (48.0)	30 (34.9)	0.0884
Structural changes of SIJs	33 (51.6)	30 (60.0)	49 (57.0)	0.5230
Erosion	28 (43.8)	22 (44.0)	40 (46.5)	0.9324
Fat metaplasia	15 (23.4)	15 (30.0)	33 (38,4)	0,1450
Ankylosis	8 (12.5)	12 (24.0)	7 (8.13)	0.0319	b0.0101;y0.0206	b0.0113
Peripheral type	52 (81.0)	44 (88.0)	77 (89.5)	0.3190
Arthritis	40 (62.5)	32 (64.0)	57 (66.3)	0.8886
Enthesitis	45 (70.3)	41 (82.0)	59 (68.6)	0.2153
Dactylitis	7 (10.9)	7 (14.0)	7 (8.13)	1
Axial and peripheral type	31 (48.43)	34 (68)	43 (50)	0.07
Drugs for treatment of SpA
Nihil	14 (21.78)	13 (26)	16 (18.6)	0.5968
NSAIDs	47 (73.43)	35 (70)	65 (75,6)	0.7765
Sulfasalazine	17 (26.56)	20 (40.0)	22 (25.6)	0.1694
Methotrexate	6 (9.37)	11 (22.0)	17 (19.8)	0.1360

Abbreviations: BM - bone marrow; NSAIDs - Non-Steroidal Anti-Inflammatory Drugs; SIJs - sacroiliac joints.

Clinical characteristics of patients and activity of SpA

Figure 2 and Figure 3 show the clinical characteristics of the patients and their SpA activity. Women were more represented than men in the symptomatic and asymptomatic ID groups (P < 0.0001), as well as in the control group (P = 0.0006) as analyzed using Fisher’s exact test (Figure 2A, 2B, and 2C, respectively). Age (Figure 2D), BMI (Figure 2E), and SpA duration (Figure 2F) were comparable across the groups. Patients with symptomatic ID were significantly younger at SpA onset than those in the control group (Figure 2G, P = 0.015, Bonferroni adjustment of P value obtained by One-way ANOVA and Tukey post-hock test).

Figure 2.

Clinical characteristics of patients with spondyloarthritis (SpA) suffering from symptomatic internal derangement (ID) of temporomandibular joint (TMJ) (group A), asymptomatic ID of TMJ (group B), and control (group C). Bar graphs show (A) sex distribution in group A, (B) sex distribution in group B, and (C) sex distribution in group C. The line graph displays (D) age, (E) body mass index (BMI), (F) duration of SpA, and (G) age of the onset of SpA in groups A, B and C. • Mean, and I mean ± 0.95 confidence interval. Levels of statistical significance (P): *0.015 (Bonferroni adjustment of P value obtained by One-way ANOVA and Tukey post-hock test); ** 0.0006 and *** < 0.0001 (Fischer exact test). • Mean, and I mean ± 0.95 confidence interval.

Figure 3.

Clinical parameters of spondyloarthritis (SpA) activity in patients with symptomatic internal derangement (ID) of temporomandibular joint (TMJ) (group A), asymptomatic ID of TMJ (group B) and control (group C). Graphs show (A) ASDAS - Ankylosing Spondylitis Disease Activity Score; (B) BASDAI - Bath Ankylosing Spondylitis Disease Activity Index; (C) DAPSA - Disease Activity Index in Psoriatic Arthritis; (D) Frequency of patients with psoriasis; (E) patients' self-estimated activity of SpA on a visual analogue scale (VAS); (F) VAS for overall pain; (G) VAS for axial pain and (H) VAS for peripheral pain in groups A, B, and C. Levels of statistical significances (P): * 0.049; ** 0.006; *** 0.002; **** 0.0008; ***** 0.0004 and ****** 0.000004 (Bonferroni test correction of P values obtained by One-way ANOVA and Tukey post-hock test). • Mean, and I mean ± 0.95 confidence interval.

ASDAS-CRP levels were higher in patients with symptomatic (P = 0.0008) and asymptomatic (P = 0.002) ID groups compared to the control (Figure 3A). BASDAI (P = 0.002) and DAPSA (P = 0.0004) scores were higher in patients with symptomatic ID compared to control (Figure 3B and Figure 3C, respectively). Patients with symptomatic ID had greater difficulties in performing total daily activities (P = 0.049) than the control group (Figure 3D). Patients' self-estimated SpA activity was significantly higher in both symptomatic (P = 0.000004) and asymptomatic (P = 0.002) ID groups than in the control (Figure 3E). Total body pain (Figure 3F) was greater in patients with symptomatic ID than in the control (P = 0.0008). Axial pain was greater in both the symptomatic (P = 0.006) and asymptomatic ID groups (P = 0.0004) compared to controls, averaging approximately 5 on a scale of 0 to 10 (Figure 3G). VAS scores for peripheral pain did not differ significantly across groups (Figure 3H).

Laboratory characteristics of patients with SpA

Figure 4 shows laboratory characteristics of patients with SpA. Erythrocyte counts were comparable across groups (Figure 4A). Hemoglobin concentration was lower (P = 0.017) in patients suffering from symptomatic ID (136 g/L [133 -138], mean [0.95 Confidence Interval]) when compared with control (141 g/L [139 -143], Figure 4B). Hematocrit was lower in patients with symptomatic ID (0.4% [0.4-0.41]) and asymptomatic ID (0.4% [0.39-0.44]) when compared with control (0.42 [0.42 - 0.43], P = 0.007, Figure 4C). Platelet counts were significantly higher (P = 0.017) in patients with symptomatic ID (274 ×10⁹/L [258 ×10⁹ - 290 ×10⁹]) when compared with control (248 ×10⁹/L [237 ×10⁹ - 260 ×10⁹], Figure 4D). Leukocyte counts (Figure 4E) and CRP levels (Figure 4F) were within normal ranges and did not significantly differ across the groups. Serum concentration of alpha-amylase was significantly higher (P = 0.017) in patients with symptomatic ID (76 IU/L [66 - 85]) than in the control group (62 IU/L [57 - 67]), (Figure 4G). ASTO was significantly higher (P = 0.049) in patients with symptomatic ID (128 IU/mL [93 - 162]) and asymptomatic ID (132 IU/mL [88 - 176]) than in the controls (79 IU/mL [61 - 96], Figure 4H).

Figure 4.

Laboratory parameters of activity of spondyloarthritis (SpA) in patients with symptomatic internal derangement (ID) of temporomandibular joint (TMJ) (group A), asymptomatic ID of TMJ (group B) and control (group C). Graphs show (A) erythrocyte count, (B) hemoglobin concentration, (C) hematocrit, (D) platelet count, (E) leukocyte count, (F) C-reactive protein (CRP), (G) serum alpha-amylase, and (H) antistreptolysin O titre (ASTO) in groups A, B, and C. Levels of statistical significance (P): * 0.049; ** 0.017; *** 0.007 (Bonferroni test correction of P values obtained using One-way ANOVA and Tukey post-hock test). • Mean, and I mean ± 0.95 confidence interval.

Discussion

Our study demonstrated for the first time that patients with SpA who suffer from IDs have exacerbated axial disease, as indicated by radiologic findings of the sacroiliac joints, laboratory findings, and rheumatological examination. Women were more represented than men, likewise in some earlier studies (11, 12). Disc displacement with reduction was the most common ID in patients with SpA, as well as in patients without SpA of appropriate age (11). Symptomatic ID presents a large burden for patients, consistent with recent data from Syrmou et al. (29) and Vrbanović et al. (11). Notably, in addition to symptomatic ID, many patients with asymptomatic ID were diagnosed using the DC/TMD protocol, particularly in patients with exacerbation of axial SpA and structural changes of the sacroiliac joints compared to controls, regardless of SpA duration. This finding aligns with the increased risk of developing TMDs in patients with r-axSpA (8). A recently published meta-analysis by Brazilian researchers also reported a higher prevalence of asymptomatic TMDs in patients with axSpA (33). This is consistent with the hypothesis that asymptomatic ID is not clinically manifested in patients with SpA, although the same immune-pathogenetic mechanism likely exists in the underlying disease, as seen in patients with symptomatic TMDs where the disease presents with all its main symptoms (34). Gut dysbiosis and frequent subclinical chronic intestinal inflammation underlie various clinical manifestations of SpA (35), including TMDs (36). Accordingly, increased serum alpha-amylase might reflect the greater proliferative capacity of small intestine epithelial cells (37), thus indicating more pronounced inflammation in patients with symptomatic than in asymptomatic ID and controls. Thus, osteoarthritis (10, 38) and, particularly, disc displacement in the TMJ (19), supported by radiological findings, can be completely asymptomatic, probably due to the lower degree of inflammation and owing to the TMJ’s large compensatory mechanisms (19, 32).

MRI is the "gold standard" in diagnosis of ID of TMJs (12). In this study, MRI of the TMJs in the patients with asymptomatic ID was not performed, as current clinical practice often assumes that such symptoms are not severe enough to impact the patient significantly. Additionally, MRI is an expensive, time-consuming procedure performed by highly trained specialists that represents an economic burden on the community. Symptomatic ID in this investigation was diagnosed clinically using the validated Axis I protocol of the DC/TMD, which has 97% specificity and 80% sensitivity for detecting painful TMDs (9, 5). This is consistent with the recruitment of patients in a recently published meta-analysis based on clinical and/or radiographic evidence of TMDs (33). The high specificity and sensitivity of the DC/TMD protocol facilitate the diagnosis of symptomatic ID (11) and the diagnosis of SpA around the age of 30 years, which is significantly earlier compared to patients with intact TMJs. This aligns with the typical onset age for painful axial SpA (39), as pain, especially chronic pain in TMJs, often prompts young adults to seek medical attention (7, 11, 15). In contrast, patients with asymptomatic ID did not experience pain in the TMJs, likely explaining why their age of SpA onset did not differ significantly from that of the control group. Thus, ID of TMJs can progress asymptomatically for some time, remaining unrecognized as part of SpA and, therefore, seems to be inadequately treated, although it can be visualized by MRI (12). This can facilitate ID progression and the development of r-axSpA. Indeed, clinical parameters reflecting SpA activity, particularly markers of axial disease such as ASDAS-CRP (27), were elevated in both asymptomatic and symptomatic IDs compared with controls, indicating an equal burden in terms of health and quality of life in both patient groups. It is well-established (23) and recently confirmed (40) that psoriatic changes in painful TMJs show consequences of chronic inflammation (erosion) and joint effusion as a sign of acute inflammation on MRI, which is consistent with higher DAPSA scores in patients with symptomatic ID in this investigation. Patients with symptomatic and asymptomatic ID groups also reported higher self-perceived disease activity and increased axial pain, although peripheral joint pain was not a dominant feature, consistent with findings in patients with r-axSpA (27). Those with symptomatic ID exhibited an elevated BASDAI alongside greater total body pain and enhanced difficulties performing all-day activities; however, these tools do not distinguish between axial and peripheral SpA activity (41).

Laboratory indicators further supported systemic inflammation in SpA patients with ID in relation to the controls. A reduction in hematocrit levels in both asymptomatic and symptomatic ID groups and a decrease in hemoglobin concentration in symptomatic ID foreshadow anemia of chronic disease, particularly in patients with symptomatic ID, which is predictive of functional impairment and axial SpA activity (42). Increased serum ASTO in both groups of patients with ID of TMD explains earlier streptococcal infection, which may have stimulated SpA activity, especially in carriers of the HLA-B27, B38, B39 and B8 genes (3).

The treatment of asymptomatic ID and their potential progression to symptomatic ID of TMJ in patients with SpA remains contentious. Progression may depend on the intensity and duration of the immune reaction in the TMJs, as observed in the progression of nr-axSpA to r-axSpA (4). In our patients, asymptomatic ID of TMJ was associated with more frequent exacerbation of r-axSpA, as resulted by ankylosis of the sacroiliac joints, found at the time of patients' recruitment, suggesting progressive axial disease. This connection between axial involvement and asymptomatic ID is supported by recent findings from de Melo-Silva et al. (33) and de Holanda et al. (8), as well as earlier studies linking occlusal interference and functional abnormalities of the cervical region and sacroiliac joints (43). Symptomatic TMDs have been associated with cervical spine pain (44) in patients with r-axSpA who tend to experience greater neck disability (32). Neck mobilization techniques have been shown to effectively improve maximal mouth opening and reduce pain in TMJs (45).

The data presented above showed the clinical implications of the research. Patients with symptomatic and asymptomatic IDs had statistically significantly increased patients' self-estimated axial pain and activity of SpA, as objectified with ASDAS and followed by the increased anti-streptolysin titre and decreased hematocrit than controls. Patients with symptomatic ID also had an earlier onset of SpA, along with increased disease activity indexes (BASDAI and DAPSA), total body pain, and difficulties in performing daily activities, increased platelet count, and serum alpha-amylase, but lower hemoglobin concentration than controls. Patients with asymptomatic ID had higher frequencies of exacerbated axial SpA and sacroiliac joint ankylosis compared to controls.

Conclusion

Both, asymptomatic and symptomatic IDs of TMJ in patients with SpA are associated with the activity of axial form of the disease, however the inflammatory process appears to be more pronounced in patients with symptomatic ID. Given the high prevalence of asymptomatic ID of TMJ in patients with SpA ongoing attention in clinical practice is needed to ensure early diagnosis of asymptomatic ID through radiologic imaging and timely treatment due to the significant burden on the health of these patients. The decision not to perform MRI on asymptomatic ID in this investigation is a limitation of this study and could have influenced patient group allocation. Another limitation could be the generalizability of the findings, since the study was conducted in a single hospital in Croatia, although the results are in line with previously published research conducted in other centers in Croatia and with those all over the world. Moreover, investigating immune mediators participating in the pathogenesis of SpA, with clinically relevant diagnostic value for asymptomatic ID, can be of particular interest for simple, economically acceptable, and timely diagnosis.