Abstract
Objective This prospective study investigates the efficacy of biologics in combination with methotrexate (MTX) or leflunomide (LEF) on juvenile idiopathic arthritis (JIA)-related temporomandibular joint (TMJ) arthritis measured by magnetic resonance imaging (MRI)-based inflammation score and deformity score.
Methods A prospective, single-center observational cohort study of 18 consecutive patients was performed between September 2018 and April 2023. Inclusion criteria were (1) diagnosis of JIA, (2) MRI-verified TMJ arthritis leading to treatment with tumor necrosis factor inhibitor (TNFi), (3) MRI at 6 months and 24 months after treatment initiation, and (4) clinical follow-up together with an MRI by a pediatric rheumatologist and an orthodontist.
Results We included 18 patients (89% female). At the time of the first MRI, median age was 13.2 years (IQR 9.9-17.4), median disease duration was 7.8 years (IQR 3.4-11.1), and 4 received MTX or LEF. During the observation period, significant improvements were observed in TMJ movement pain (P = 0.01), morning stiffness (P = 0.004), opening capacity (P = 0.03), and maximal incisal opening (P = 0.006). The inflammation score decreased significantly from a median of 2 (IQR 1-3) at baseline to a median of 1 (IQR 0-2) at 24 months (P = 0.009). In 17 of 36 TMJs (47%), the deformity score improved or remained stable and no significant increase in the median score was observed.
Conclusion This is the first prospective, observational study with evidence to support that the orofacial signs, symptoms, and MRI-derived inflammation score in TMJ arthritis can be reduced by treatment with TNFi.
Within the last 2 decades, the treatment of juvenile idiopathic arthritis (JIA) has been intensified and hence, the outcome has advanced significantly with the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) targeting proinflammatory cytokines or cell-cell interactions.1,2 Tumor necrosis factor inhibitors (TNFi) have become a mainstay and the most prescribed biologic agent for JIA, often used as an add-on therapy to conventional DMARDs (cDMARDs).3-5
Recently, the American College of Rheumatology treatment guidelines for JIA have been updated6 and consensus-based recommendations for the management of JIA-related temporomandibular joint (TMJ) arthritis from the Temporomandibular Joint Juvenile Arthritis Working Group (TMJaw) have been published.7 For the first time, a therapeutic approach for TMJ arthritis has been introduced, although there is a paucity of evidence-based recommendations.6,7
In the era of biologics, TMJ involvement defined by abnormalities presumed to be the result of TMJ arthritis remains common in JIA, but its prevalence is not well established. Although some studies indicate a prevalence of 30% to 40%, these findings are limited by a lack of clear distinction between the terms “TMJ involvement” and “TMJ arthritis,” which may affect the accuracy of the results. According to consensus guidelines on terminology, “TMJ arthritis” refers to the presence of “active” TMJ arthritis, whereas “TMJ involvement” refers to the sequelae indicating current/previous TMJ inflammation.8 TMJ arthritis and involvement may lead to TMJ disorders and orofacial pain, TMJ morning stiffness, limitation on chewing, dysfunctions such as decreased or asymmetric mouth opening, dentofacial deformities, narrowing of the upper airways, and a significant deterioration of quality of life that can persist into adulthood.9-20 Despite the growing body of research on TMJ-related conditions in JIA, no high-level evidence exists to guide the treatment of TMJ arthritis. There is currently a lack of randomized controlled or open-label follow-up studies for comparison of the effectiveness of biologic treatment for TMJ arthritis, and in general, no prospective studies exist, as stated in several reviews and guidelines.6,7,21-23 Traditionally, TMJ arthritis has been treated with intraarticular corticosteroid injections (IACI). However, the effect of IACI on TMJ arthritis is short-lived and does not prevent the development of TMJ deformity and growth restraint of the mandible in skeletally immature patients and may lead to the development of intraarticular calcifications and ankylosis.24-27 Additionally, intraarticular injection with TNFi has been reported in 1 study that did not show significant effect.28 Studies on systemic treatment such as methotrexate (MTX) for TMJ arthritis are scarce.29 Bollhalder et al30 published a retrospective study on serial magnetic resonance imaging (MRI) of the TMJ in 38 patients with a ≥ 2-year interval using a standardized grading system for inflammation levels.31,32 The study30 supported a beneficial effect of systemic medical treatment on inflammation (MTX was given in 92% of patients and MTX or leflunomide [LEF] in combination with biologics in 53%) and documented that in patients with systemic treatment, mandibular ramus growth was maintained, in contrast to those treated with IACI.
Accordingly, much uncertainty still exists about the effect of DMARDs on TMJ arthritis, growth disturbances of the mandibular ramus, and osseous deformities of the mandibular condyle and glenoid fossa. Hence, the aim of this prospective, single-center cohort study was to investigate the changes in the following variables at baseline, and after 6 months and 24 months: (1) orofacial symptoms and dysfunction; (2) MRI-verified inflammation; (3) osseous TMJ morphology; and (4) correlations between symptoms, dysfunctions, and MRI findings.
METHODS
The present longitudinal, prospective, observational cohort study was based on data from 18 consecutive patients enrolled from the Department of Pediatric and Adolescent Medicine, Aarhus, University Hospital, Denmark, between September 2018 and April 2021. All patients had standardized orofacial examinations performed at the Regional Specialist Craniofacial Clinic, Section of Orthodontics, Department of Dentistry and Oral Health, Aarhus University.
A contrast-enhanced MRI was initiated if the patients had symptoms or clinical findings indicating suspicion of TMJ arthritis at any time during their disease course. We assigned patients with MRI-verified TMJ arthritis a step-up treatment to receive cDMARDs (MTX, LEF) and TNFi, with a 2-year follow-up observation. If the patient was already receiving MTX or LEF at the time of diagnosis of TMJ arthritis, a TNFi was added.
Inclusion criteria were as follows: (1) diagnosis of JIA according to the International League of Associations for Rheumatology criteria33; (2) contrast-enhanced MRI-verified TMJ arthritis leading to initiation of TNFi in either cDMARD-naïve children or as an add-on to cDMARDs already prescribed prior to the MRI; (3) a craniofacial MRI 6 months (± 1 month) and 24 months (± 1 month) after initiation of TNFi; (4) standardized clinical assessment along with an MRI (± 1 month) by a pediatric rheumatologist and an orthodontist with special expertise in orofacial manifestations of JIA.
Exclusion criteria included the following: (1) previous TMJ corticosteroid injection or need for injection during the follow-up time; (2) previous jaw surgery; (3) trauma, syndromes, or comorbidities that potentially could affect the dentofacial growth; and (4) use of bDMARDs within 12 months before the diagnosis of TMJ arthritis.
Background information was retrieved from the medical records, including date of birth; sex; age at JIA onset and at inclusion; JIA category; active joint count at diagnosis and at inclusion; antinuclear antibody, rheumatoid factor, HLA-B27 status; and medication history.
Clinical orofacial examination of the TMJ. The standardized clinical examinations were performed according to the consensus-based recommendations by TMJaw.34 Orofacial symptoms were outlined as patient-reported conditions related to TMJ arthritis or involvement. JIA-related orofacial dysfunction denoted physician-reported functional abnormalities related to TMJ arthritis or involvement, and dentofacial deformity referred to arthritis-related alterations of the jaw anatomy diagnosed by clinical examination. The terminology of the current project adheres to the JIA-TMJaw consensus-based recommendations.8 The examination was done by orthodontists specially trained for TMJ examinations in patients with JIA (AK, PS, TKP). The medical treatment was initiated by MG or CH after a consensus decision was obtained.
MRI scoring. In a closed mouth position, contrast-enhanced MRI was performed at 1.5 Tesla (Siemens Avanto) according to protocol recommendations by TMJaw,35 always including a precontrast fluid-sensitive sequence and T1-weighted fat-saturated sequences (Supplementary Table S1, available with the online version of this article) acquired immediately after intravenous injection of a single dose of gadolinium-based contrast agent (0.1 mmol/kg body weight gadobutrol). The MRI studies were evaluated by a pediatric radiologist (CJK) blinded to the clinical information. The evaluation was made in adherence with 2 previously published scoring systems: progressive (Swiss) and additive (Outcome Measures in Rheumatology group).31,36 Reliability and validation of the items within the scoring systems have been carried out.37
The mandibular posterior height (MPH) was measured parallel to the tangent at the posterior border of the ramus between the most cranial point of the condyle and lower border of the ramus mandibulae.38
According to the progressive scoring system,31 TMJ inflammation was graded based on the presence of joint effusion (0-1), degree of joint enhancement (0-1), presence of synovial thickening (0-1), and pannus (0-1), with a total score of 4. TMJ arthritis was defined as TMJ inflammation score ≥ 1. The progressive deformity score (grade 0-4) is based on flattening of the mandibular condyle and mandibular fossa, presence and size of erosions, and destruction of the bony joint structures.31
When applying the additive scoring system,35 the additive inflammation domain was assessed by the presence of bone marrow edema (0-1), bone marrow enhancement (0-1), effusion (0-2), joint enhancement (0-2), and synovial thickening (0-2), with a total score of 8. The additive damage domain included condylar flattening (0-2), erosions (0-2), and disk abnormalities (0-1), with a total score of 5.
When analyzing the correlation between maximal incisal opening (MIO) and inflammation or deformity scores, the highest score among the left and right sides of inflammation or deformity was used. The MIO was dichotomized using a cutoff point < −2 SDs from the mean of age-related, normative values.39
Statistics. Descriptive statistics were used to summarize cohort characteristics. Relative proportions and 95% CIs were used to assess the relationship between frequencies. Friedman test was used to examine the differences between ≥ 3 matched sets of frequencies or proportions in binary, matched samples. McNemar test was used for analyzing the differences between matched samples in terms of frequencies or proportions. Additionally, Spearman test was applied to analyze the correlation between 2 variables in ordinal data.
RESULTS
A total of 18 consecutive patients, 89% female and with a median age at diagnosis of TMJ arthritis of 13.2 years (IQR 11.3-16.9), were included in the study. None were excluded during the 2 years because of missing MRIs within the specified time frame, discontinued biologics, or other reasons (Supplementary Figure S1, available with the online version of this article). All patients had at least 3 MRIs performed: (1) at diagnosis of TMJ arthritis before the start of TNFi treatment, (2) at a median of 6.5 months (IQR 6-7.5) after treatment initiation, and (3) at a median of 23.9 months (IQR 23.5-24.6) after treatment initiation. The clinical orofacial examination was performed at a median of −6.5 days (IQR −24 to 11 days) from the MRI scans. Additional background information is presented in Table 1.
Characteristics of the JIA cohort at the time of TMJ arthritis, verified by MRI.
Treatment. The medications used prior to inclusion are detailed in Supplementary Figure S2 (available with the online version of this article). Before their diagnosis of TMJ arthritis, 4 patients had been treated with TNFi, which was stopped 1.1, 2.2, 2.3, and 3.7 years before inclusion. At the time of inclusion, 3 of the patients were already treated with MTX for disease activity other than TMJ arthritis and 1 patient received LEF, when TMJ arthritis was diagnosed. TNFi was additionally prescribed (Supplementary Figure S2). For the additional 14 patients, MTX or LEF was started together with TNFi because of the MRI findings of TMJ arthritis. In addition, all patients were treated with an orthopedic dental splint (distraction splint) or a stabilization splint at the start of biologic treatment. In 1 of the 18 patients, an arthrocentesis with saline of the TMJ was performed because of excessive pain, but none had steroids injected into the TMJs during the study period. The arthrocentesis was performed 4 months after initiation of TNFi.
MTX was switched to LEF during the 2-year period in 4 patients because of gastrointestinal side effects and/or elevated alanine transaminase. During the 2-year follow-up period, 1 patient switched from TNFi to an interleukin (IL)-17 inhibitor (secukinumab) because of presumed TNFi-associated psoriasis diagnosed by a dermatologist. Two patients switched from TNFi to tocilizumab, indicated by abnormal liver transaminases in 1 patient and flare of arthritis in peripheral joints in the other. None of the 3 switchers changed treatment as a result of treatment failure because of TMJ arthritis. The TMJ inflammation scores at baseline between the switchers and the nonswitchers were similar (progressive inflammation score median of 2 in both groups and additive inflammation score median of 4 in both groups). In addition, the median deformity scores for both the progressive and the additive scores in the 2 groups were comparable (median 2.5 for switchers and 2 for nonswitchers). Age at diagnosis of TMJ arthritis was similar (median 12.9 yrs vs 13.2 yrs).
Orofacial symptoms. Patient-reported symptoms were common findings (Table 2). In total, 15 of 18 (83%) had at least 1 symptom at baseline, which decreased to 10 of 18 (56%) at 6- and 24-month follow-ups. The most frequent symptom at baseline was pain on movement. The number of symptoms decreased significantly during the 24 months of follow-up, from a median of 5 (IQR 3-7) to a median of 1 (IQR 0-3; P = 0.009). The symptoms that improved significantly during the observation period were pain on movement (P = 0.01), morning stiffness (P = 0.004), and the reported opening capacity (P = 0.03). The patient-reported chewing capacity, masticatory muscle pain, crepitation, clicking, and locking did not change during the observation period.
The prevalence of orofacial symptoms and orofacial dysfunctions in patients with JIA at 3 timepoints (N = 18 patients).
Orofacial dysfunctions. At all 3 timepoints, 18 of 18 (100%) patients had at least 1 sign of dysfunction, with reduced translation being the most frequent finding at all 3 timepoints (56%). The dysfunction that improved significantly during the observation time was MIO both with and without pain (P = 0.006 and P = 0.009, respectively; Table 2). During the 2 years, the MIO without pain increased from a median of 39.5 mm (IQR 32-43) to 48.5 mm (IQR 42-50), and MIO with pain increased from a median of 43 mm (IQR 38-49) to 49 mm (IQR 45-50).
MRI findings. At baseline, 13 of 18 (72%) patients had MRI signs of bilateral and 5 of 18 (28%) of unilateral TMJ arthritis. The prevalence of TMJ arthritis (progressive inflammation score ≥ 1) after 6 months and 24 months was 29 of 36 (81%; 95% CI 67-94%) joints and 25 of 36 (69%; 95% CI 49-81%) joints, respectively (Table 3). In general, the progressive inflammation score decreased significantly from a median of 2 (IQR 1-3) at baseline to a median of 1 (IQR 0-2) at 24 months (P < 0.01; Figure 1A). Likewise, the additive inflammation scores also decreased significantly (P < 0.001; Figure 1B). In total, 11 of 36 (31%) TMJs had a progressive TMJ inflammation score of 0 after 2 years of treatment (Table 3) and, in more than half (21 of 36 [58%]) the TMJs, the score improved (Table 4).
(A) Progressive inflammation and deformity score at baseline, 6 months, and 24 months after treatment initiation. (B) Additive inflammation and deformity score at the 3 timepoints.
The progressive and additive inflammation and deformity score on MRI at 3 timepoints (N = 36 TMJs).
Changes in progressive inflammation and deformity score in 36 TMJs of 18 patients from diagnosis of TMJ arthritis to the last follow-up after 24 months.
Increased disease activity in peripheral joints occurred in 2 of the patients with improved TMJ inflammation.
The MPH increased by a median of 2 mm during the 2 years of follow-up (IQR 0.1-3.3; P < 0.001; Figure 1A).
At initial MRI, 7 of 18 (39%) patients had unilateral condylar deformity, 10 of 18 (56%) had bilateral deformity, and 1 patient had no deformity. After 2 years of treatment, 8 of 18 (44%) continued having unilateral deformity, 8 of 18 had (44%) bilateral deformity, and 2 of 18 (11%) did not have any deformity (1 unilateral deformity dissolved to no deformity and 1 patient deteriorated from unilateral to bilateral deformity).
The prevalence of TMJ deformity (progressive deformity score ≥ 1) was present in 25 of 36 (69%; 95% CI 52-84) TMJs at baseline and at last follow-up in 27 of 36 (75%; 95% CI 58-88%) TMJs. In almost half of the TMJs, the progressive deformity score improved or was stable (2 of 36 [6%] and 15 of 36 [42%], respectively); however, 19 of 36 (53%) deteriorated in progressive deformity score during the study period. The progressive deformity scores showed no significant difference, with a median of 2 (IQR 0.5-3; P = 0.31) among the 3 timepoints (Figure 1A). When applying the additive deformity score, it deteriorated from 2 to 3 (P = 0.009). The inflammation score did not correlate with the deformity score either at baseline (rs = 0.20; P = 0.25) or at 24 months of follow-up (rs = 0.10; P = 0.56).
Correlations between symptoms, clinical findings, and MRI findings. Patient-reported locking and crepitation of the TMJ correlated with the degree of deformity (Table 5). We found no correlation between the prevalence of orofacial symptoms and the degree of inflammation shown by MRI. The degree of inflammation on MRI was significantly correlated to decreased translation (rs = 0.46; P = 0.004; Table 5). Additionally, there was a nonsignificant correlation between the degree of inflammation and crepitation or muscle pain on palpation (P = 0.08 and P = 0.09, respectively).
Correlations between symptoms, clinical findings, and MRI findings at baseline (N = 18).
Regarding dysfunctions and the degree of deformity, the only significant correlation was reduced translation (P = 0.05; Table 5). We found no correlation between reduced MIO and the deformity score (Table 5).
DISCUSSION
With this longitudinal, prospective study, we investigated the effectiveness of systemic treatment on JIA-associated TMJ arthritis. The main findings of the study during the course of escalated systemic treatment were (1) a significant decrease in some orofacial symptoms; (2) a significant improvement in TMJ function related to MIO; (3) a significantly reduced inflammation score on MRI with nearly one-third (31%) of the TMJs having a score of 0 at the final follow-up; and (4) improvement or stable deformity score in 47% of the TMJs.
Across the literature, several studies have described how orofacial symptoms and clinical findings are common signs in patients with JIA-related TMJ arthritis.9,11,21,23,40 Although it may seem logical to expect a correlation between the severity of symptoms, dysfunctions, and MRI changes of TMJ arthritis, this relationship has not been adequately displayed.41,42
In our study, we found that symptoms of TMJ arthritis were commonly reported by patients; however, no symptoms correlated with the degree of inflammation shown on MRI. These findings indicate a noticeable inconsistency between the reported symptoms, dysfunctions, and the severity of MRI-verified TMJ arthritis. This suggests that clinical findings may not always be solely attributed to inflammation but can also be a result of internal mechanical disruptions caused by condylar deformity. In this context, the role of central sensitization remains unclear. This inconsistency between reported symptoms and MRI-verified severity of TMJ arthritis has been noted by other researchers, such as Kristensen and Scolozzi et al.43,44 Scolozzi et al performed a retrospective study of 101 patients with a mean age of 12.8 years and reported that 61% had MRI-verified TMJ arthritis and the most common symptom was pain, which is consistent with our findings. They found reduced MIO as the only clinical finding associated with the severity of TMJ arthritis. In our study, we did not find evidence supporting this as we only discovered a correlation to reduced translation. However, translation was not investigated by Scolozzi et al.44 They used an in-house scoring system for the MRI findings and Helmiko dysfunction index, which is not validated for children with JIA.45
Of interest, we found that all except 1 patient had TMJ deformity at the diagnosis of TMJ arthritis. This calls for even earlier diagnosis of TMJ arthritis, so deformities can be prevented. However, this can be a challenge because of the discrete symptoms the patients experience. There is a need for identification of biomarkers or risk factors that can assist in identifying the inflammatory process early on. In our cohort, TMJ arthritis was diagnosed at a median of 7.8 years after the JIA diagnosis, which might have had a negative effect on the deformity.
Bollhalder et al30 performed a retrospective study on 38 patients with JIA and TMJ involvement, with a follow-up of a median of 3.6 years. The study population was younger than in the present study (median 9.0 yrs vs 13.2 yrs). The patients had MRI-verified TMJ involvement (either active arthritis or deformities presumed to be related to arthritis) and were receiving DMARDs (47% on cDMARD monotherapy with MTX, LEF, or hydroxychloroquine, and 53% on combination therapy with biologics, primarily TNFi but also anti-IL-6, systemic corticosteroids, and azathioprine). Although they did not provide details about symptoms,30 our findings support the observed improvements in MIO from the beginning of our present study to the last follow-up. This does not account for a normal average MIO increase of 1.2 mm per year in this age group.39 Further, our results are consistent with the finding by Bollhalder et al30 that there is no correlation between TMJ pain upon palpation and the severity of inflammation or deformity. The study by Bollhalder et al,30 being the first in the biologic era, concluded that immunosuppressive treatment has the potential to reduce MRI-verified TMJ inflammation; however, they used variable intervals between the MRI follow-ups, used variable treatment modalities, had only 71% of patients with TMJ arthritis at baseline, and had 50% of patients starting systemic treatment 2.3 years before the first MRI.
Bollhalder et al30 found maintenance of the MPH after systemic treatment. We found a possible increase in height by a median of 2 mm, indicating a normalized vertical mandibular growth and development. However, uncertainties with the measurement method, a lack of a control group, and variations in growth potential because of different ages among the patients impaired the interpretation in our study. Bollhalder et al did not report on changes in the degree of deformity.30
In our study, we found 31% of patients had an inflammation score of 0 after 2 years of systemic treatment. For comparison, Bollhalder et al found 47.4% of patients with a score of 0 after 3.6 years.30 However, there is ongoing uncertainty regarding the clinical implications of not reaching a score of 0 following 2 years of systemic treatment. Microtrauma caused by overloading and internal joint derangements in the severely deformed TMJ might generate a certain level of inflammation detected by MRI. The significance of this outcome, or lack thereof, is still not completely understood. Further research and analysis are needed to better comprehend the potential implications and consequences of not attaining a score of 0 after undergoing systemic treatment for 2 years.
The main strength of the present study is the prospective design with fixed intervals for MRI and standardized clinical orofacial examinations and treatment modalities at inclusion.
Contrast-enhanced MRI remains the gold standard for diagnosing TMJ arthritis. However, interpretation of the images is subjective. To overcome this, we have used 1 expert radiologist (CJK) in the field blinded for any clinical information. Further, the reliability of the inflammation and deformity scoring system used in this study has previously been published.32,35-37 We also used standardized terminology and standardized clinical examination.8
A limitation is the small sample size. Further, 3 patients had to switch from TNFi to another biologic treatment with secukinumab or tocilizumab during the study, and another patient had an arthrocentesis performed during the study, which might have influenced the pain and inflammation scores. As a result of the limited sample size, it would be inappropriate to make any definitive conclusions about the effectiveness of the various medications.
Another cautionary note is that the results can be attributed to the natural fluctuation of TMJ arthritis and symptoms. Without a control group, any definitive statements cannot be made, and this should be taken into consideration when evaluating our results.
In conclusion, systemic treatment of TMJ arthritis in longer-standing JIA with biologics reduced symptoms and significantly improved MIO during the 2 years of observation in this cohort. The inflammation score on MRI was significantly improved, and in almost 50%, the deformity score was improved or stabilized. Reduced condylar translation may be an indication of TMJ arthritis during the clinical examination and warrants additional attention. In the future, randomized controlled studies are warranted to ensure the most effective initial treatment option for TMJ arthritis in patients with JIA.
Footnotes
CONTRIBUTIONS
PS: study design and conceptualization, formal analysis, data interpretation, writing the initial draft; CJK: study design and conceptualization, reading MRIs, data interpretation, reviewing and editing final draft; CH: study design and conceptualization, inclusion of patients and data collection, reviewing and editing final draft; AK: study design and conceptualization, inclusion of patients and data collection, reviewing and editing final draft; TKP: study design and conceptualization, inclusion of patients and data collection, data interpretation, reviewing and editing final draft; TH: study design and conceptualization, data interpretation, reviewing and editing final draft; MG: study design and conceptualization, formal analysis, supervision, inclusion of patients and data collection, data interpretation, reviewing and editing final draft.
FUNDING
The study has not received any financial support or other benefits from commercial sources and no funding was received for the study.
COMPETING INTERESTS
The authors declare no conflicts of interest relevant to this article.
ETHICS AND PATIENT CONSENT
This project was approved by the regional legal office, the Danish Health Authorities, and permission was given by the Data Protection Agency (J.nr. 2022-522-0516 Dok.nr. 550654). According to Danish legislation, the study is classified as a prospective, observational quality assurance study of the standard procedure and does not require approval from the ethics committee because of the observational design that does not deviate from our regular clinical practice. All invited patients chose to participate.
- Accepted for publication November 20, 2024.
- Copyright © 2025 by the Journal of Rheumatology
REFERENCES
SUPPLEMENTARY DATA
Supplementary material accompanies the online version of this article.
