To our knowledge, this is the first prospective study validating and using two recently published MRI scoring systems to assess the efficacy and safety of IACs in the TMJ in adolescents with JIA. We found that a single IAC in combination with systemic therapy may improve short-term and long-term MRI-assessed inflammation and MIO, even though pain and MRI-assessed damage did not improve significantly.
Clinical outcomes: Pain and MIO
In our study the pain-index score improved in 6/11 patients at 2-months follow-up and 8/10 patients at the 2-year follow-up median 22 months after IACs to the TMJs. Pain was one of the main indications for performing the IACs in our study, and the pain-index score is reported to be a valid and sensitive outcome measure in TMJ arthritis (17). Improvement in pain is reported in most retrospective studies in JIA children based on medical chart information or the patients' self-assessment of pain, where improvement in orofacial symptoms is seen in 67–100%, follow-up ranging from mean 3 to 52 months after TMJ-IACs (15, 24, 42-44). However, none of these studies used quantified pain reports. Stoustrup et al. used the validated pain-index score in 13 JIA children receiving IACs to the TMJs in a prospective pilot study (17). They found significant short-term pain reduction, but remitting pain at long-term follow-up, indicating a loss of the initial effect of the IACs (17). Our study shows a trend for improvement in pain at the 2-month follow-up which is sustained during the observation period over two years (not statistically significant). The sustained tendency of reduced pain may be due to the systemic medication (DMARDs and biologics), which was changed in 10/15 patients in our study. Five of the 11 patients were in remission at the 2-year follow-up, indicating an effect of the treatment, which included IACs and the systemic medication. The sampling procedure with lavage may also induce improvement, Olsen-Bergem et al found that arthrocentesis with lavage in patients with TMJ arthritis and JIA might be beneficial for the treatment outcome, and that steroids did not add additional effect to the outcome (45). The natural fluctuation with waxing and waning disease activity over time often seen in JIA must also be considered (46).
We found that MIO improved in 9 of 13 patients at 2-months follow-up, and in 9 of 11 patients between baseline and 2-year follow-up after IACs to the TMJs. This is similar to retrospective studies where improvements in MIO are reported between 2.7 and 6.6 mm (15-18, 24, 42-44). However, measurements of MIO are associated with much variation (47, 48), increase with age, and show a wide normal range in children of the same age (49). In our study we used standardized protocols and calibration of the examiners in order to avoid measurement bias (31) (32). Stoustrup et al. found the smallest detectable difference in repeated MIO measurements in patients with JIA to be 5 mm when a strict and standardized measurement protocol with repeated measurements were applied (48). A clinically relevant improvement ≥5 mm was found in our study in 4 of 13 patients between baseline and 2-months follow-up and in 5 of 11 between baseline and 2-year follow-up after IACs. Our median improvement in MIO may be influenced by random error within the measurement procedure. Moreover, MIO at baseline was not severely reduced, and we doubt that this small change in MIO is a clinically relevant effect on jaw function even if statistically significant.
MRI outcomes
MRI-verified TMJ-arthritis is not always accompanied by clinical symptoms from the TMJ.
A systematic review concluded that no single clinical finding could accurately predict MRI findings consistent with arthritis (50). The measurements in our study therefore included both standardized clinical assessment tools with pain reports, MIO, and MRI to verify TMJ-arthritis both at both baseline and follow-up.
A problem in evaluating outcome after IACs has been the use of qualitative assessments and lack of consistent definitions and MRI-scoring systems (36, 37). In the assessment
of inflammation in our study, the additive inflammatory domain improved significantly between baseline and the 2-months follow-up. Improvement was seen in 6/13 patients as compared to 4/13 patients in the progressive inflammation score. At the 2-year follow-up, 7 of the 10 patients improved significantly in the additive inflammatory domain and 3 were stable, whereas in the progressive inflammation score 5 of 11 patients improved at 2-year follow-up, but no overall significant improvement was seen.
The improvement in MRI-assessed inflammation is in accordance with Resnick et al. who found reduced synovial enhancement in their retrospective study of 29 JIA patients with 50 TMJs, even if only 18% of their TMJs experienced complete resolution of synovitis (18). Most studies of IACs to the TMJs in patients with JIA report an MRI improvement of 48-83% regarding inflammation (15, 16, 23, 24). However, these studies used different definitions of MRI improvement than the MRI scoring systems used in our study (36, 37).
We found no improvement in the additive damage domain comprising condylar flattening, erosions and disc abnormalities or in the progressive osseous deformity score. Importantly, increased damage was not found at the group level, even if 2 of the 10 patients with 2-year follow-up in our study worsened in the additive damage domain and 1 of 11 patients worsened in the progressive score for osseous deformity. Furthermore, two patients with only 1-year follow-up worsened. We cannot discern the effect of IACs from the effect of ongoing arthritis, even if both patients with 2-year follow-up had repeated IACs once unilaterally. MRI showed persistent inflammation at 2-year follow-up in both these patients. Three patients improved from baseline to 2-year follow-up and one patient improved at 1-year follow-up. Furthermore, another patient who worsened in bone damage between injection and 2-months follow-up, improved at the 2-year follow-up.
Stoll et al. (16) found in 15/47 (32%) of the TMJs injected with IACs, evidence of new-onset erosion and flattening. Arabshahi et al.(15) also reported post-therapeutic progression with bony resorption in three (16%) of 19 TMJs. Ringold et al. (42) reported that 10/15 (67%) of the patients receiving IACs therapy showed signs of worsening. Lochbuhler et al. (22) reported progressive osseous deformation in 45 of 66 TMJs in their cohort of children with JIA and TMJ arthritis receiving repeated injections (mean 2.4±1.4 IACs per joint, range 0-7).
The additive inflammatory MRI score consists of five domains. The fact that this additive inflammatory scoring system have scores 0 to 2 (maximum 2) for joint effusion, joint enhancement and synovial thickening, while bone marrow edema, bone marrow enhancement scores maximum 1, place less emphasis on the two latter domains. The same applies to the additive damage MRI score consisting of three domains, where condylar flattening and erosions score 0 to 2, and disc abnormalities score maximum 1 if present. It is also unclear how the progressive system was constructed with regard to relative weighting of findings. Whether this emphasis is based on data analyses or constructed for simplicity is not stated in the publications of the scores.
The progressive inflammation and osseous deformity scores incorporate several features into one score in a progressive manner. In one of the four papers (36) where the system has been presented it is stated that the most severe change is the deciding feature, however, in the three others (37-39) this statement is not included. Deciding the most severe change can be challenging, and our interpretation of the system was that a given score was reliant on fulfillment of the previous level of pathology. This may have lowered the progressive osseous deformity score if erosions were present without co-occurrence of flattening, and the progressive inflammation score if bone marrow oedema was present without increased synovial enhancement. There was some variation in the kappa coefficients, both between right and left side in both systems and between the different variables of the additive system. The best intra-observer agreement was found for disc abnormalities and synovial thickening, in the latter with substantial and almost perfect agreement. The repeatability varied somewhat more in our study compared to the report by Tolend et al. (36). Assessment variations may have influenced the outcome, particularly because of the small study sample. Furthermore, the scoring systems have not previously been clinically validated and their ability to detect change has not been examined.
Whether MRI should be performed to assess the effect of interventions in TMJ remains unanswered. In Table 4 there is no uniform pattern, but a trend that the MRI changes in inflammatory scores parallell the clinical improvement. Based on our data, clinical experience and the literature, repeated MRI might be indicated primarily if clinical symptoms and signs do not improve.
Table 4. Summary characteristics, use of medication at baseline and outcome-response during 2-year follow-up in adolescents with juvenile idiopathic arthritis (JIA) (n=15) receiving intraarticular corticosteroids (IACs) to the temporomandibular joints (TMJs) (n=22).
Case
|
|
Age Onset
|
Age
Inj
|
Dose inj (mg)
|
Medic (T0)
|
Medic (T1)
|
Medic (T2)
|
Medic (T3)
|
MIO
|
Pain index
|
MRI additive inflammatory domain*
|
MRI
Progressive inflammation*
|
MRI additive damage domain*
|
MRI progressive osseous deformity*
|
Comments
|
1
|
M
|
10
|
10
|
6
|
MTX
|
MTX
|
MTX
|
|
T0: 48
T1: 42
T2: 48
T3: -
|
T0: 6
T1
T2: 2
T3: -
|
T0: 6
T1: 4
T2: 6
T3: -
|
T0: 3
T1: 3
T2: 4
T3: -
|
T0: 3
T1: 4
T2: 4
T3: -
|
T0: 3
T1: 3
T2: 4
T3: -
|
Bilateral IACs
Mandibular trauma between T1 and T2
|
2
|
F
|
17
|
17
|
8
|
MTX
|
BioCo
|
BioCo
|
BioCo
|
T0: 40
T1: -
T2: 37
T3: -
|
T0: 0
T1: -
T2: -
T3: -
|
T0: 3
T1: 2
T2: 5
T3: 1
|
T0: 3
T1: 2
T2: 3
T3: 1
|
T0: 4
T1: 4
T2: 3
T3: 3
|
T0: 3
T1: 3
T2: 3
T3: 3
|
Unilateral IACs
|
3
|
F
|
11
|
11
|
8
|
MTX
|
MTX
|
BioCo
|
|
T0: 32
T1: 35
T2: 30
T3: -
|
T0: 9
T1: 0
T2: 0
T3: -
|
T0: 5
T1: 5
T2: 5
T3: -
|
T0: 3
T1: 3
T2: 3
T3: -
|
T0: 3
T1: 3
T2: 2
T3: -
|
T0: 3
T1: 2
T2: 0
T3: -
|
Unilateral IACs
|
4
|
F
|
13
|
14
|
20
|
No DMARD
|
No DMARD
|
No DMARD
|
No DMARD
|
T0: 44
T1: 48
T2: 41
T3: 47
|
T0: 0
T1: 0
T2: 9
T3: 0
|
T0: 4
T1: 2
T2: -
T3: -
T4: -
|
T0: 4
T1: 1
T2: -
T3: 1
T4: 2
|
T0: 2
T1: 4
T2: 5
T3: 4
T4: 4
|
T0: 2
T1: 2
T2: 3
T3: 3
T4: 3
|
Unilateral repeated IACs
(13 months interval)
|
5
|
F
|
9
|
15
|
20
|
BioCo
|
|
BioCo
|
|
T0: 48
T1: -
T2: -
T3: -
|
T0: 3
T1: -
T2: -
T3: 0
|
T0: 6
T1: -
T2: 6
T3: -
|
T0: 3
T1: -
T2: 3
T3: -
|
T0: 1
T1: -
T2: 4
T3: -
|
T0: 0
T1: -
T2: 2
T3: -
|
Unilateral IACs
|
6
|
F
|
9
|
14
|
10
|
BioCo
|
BioCo
|
BioCo
|
BioCo
|
T0: 46
T1: 45
T2: 47
T3: 47
|
T0: 5.5
T1: 2
T2: 0
T3: 0
|
T0: 1
T1: 1
T2: 1
T3: 1
|
T0: 1
T1: 1
T2: 1
T3: 1
|
T0: 0
T1: 0
T2: 0
T3: 0
|
T0: 0
T1: 0
T2: 0
T3: 0
|
Bilateral IACs
|
7
|
F
|
2
|
15
|
20
|
No DMARD
|
No DMARD
|
No DMARD
|
MTX
|
T0: 36
T1: 44
T2: 44
T3: 44
|
T0: 36
T1: 10
T2: 6
T3: 0
|
T0: 3
T1: 3
T2: 3
T3: 1
|
T0: 1
T1: 1
T2: 2
T3: 1
|
T0: 1
T1: 2
T2: 1
T3: 1
|
T0: 0
T1: 1
T2: 0
T3: 0
|
Bilateral IACs
|
8
|
F
|
15
|
16
|
40**
|
No DMARD
|
No DMARD
|
MTX
|
|
T0: 45
T1: 46
T2: 50
T3: -
|
T0: 0
T1: 0
T2: 12
T3: -
|
T0: 2
T1: 2
T2: 2
T3: -
|
T0: 2
T1: 2
T2: 2
T3: -
|
T0: 4
T1: 4
T2: 4
T3: -
|
T0: 2
T1: 2
T2: 2
T3: -
|
Unilateral IACs
|
9
|
F
|
0
|
15
|
20
|
BioCo
|
BioCo
|
BioCo
|
No DMARD
|
T0: 49
T1: 54
T2: 54
T3: 45
|
T0: 0
T1: 5
T2: 0
T3: -
|
T0: 2
T1: 0
T2: 2
T3: 2
|
T0: 2
T1: 0
T2: 2
T3: 2
|
T0: 4
T1: 2
T2: 2
T3: 2
|
T0: 2
T1: 2
T2: 2
T3: 2
|
Unilateral IACs
|
10
|
F
|
15
|
16
|
20
|
No DMARD
|
No DMARD
|
MTX
|
MTX
|
T0: 45
T1: 44
T2: 49
T3: 48
|
T0: 12
T1: 22.5
T2: 0
T3: 6
|
T0: 5
T1: 6
T2: 4
T3: 2
T4: 3
|
T0: 3
T1: 3
T2: 3
T3: 1
T4: 3
|
T0: 3
T1: 3
T2: 3
T3: 4
T4: 3
|
T0: 3
T1: 3
T2: 3
T3: 3
T4: 3
|
Unilateral repeated IACs
(11 months interval)
|
11
|
M
|
11
|
16
|
20
|
No DMARD
|
No DMARD
|
No DMARD
|
No DMARD
|
T0: 55
T1: 55
T2: 62
T3: 63
|
T0: 0
T1: 0
T2: 0
T3: 0
|
T0: 5
T1: 4
T2: 2
T3: 5
|
T0: 2
T1: 1
T2: 1
T3: 2
|
T0: 3
T1: 3
T2: 3
T3: 3
|
T0: 3
T1: 2
T2: 2
T3: 2
|
Unilateral injection
|
12
|
M
|
8
|
9
|
10
|
BioCo
|
BioCo
|
BioCo
|
BioCo
|
T0: 34
T1: 40
T2: 41
T3: 45
|
T0: 7.5
T1: 0
T2: 0
T3: 0
|
T0: 7
T1: 3
T2: 1
T3: 0
|
T0: 3
T1: 3
T2: 1
T3: 0
|
T0: 0
T1: 0
T2: 0
T3: 0
|
T0: 0
T1: 0
T2: 0
T3: 0
|
Bilateral IACs
|
13
|
F
|
14
|
15
|
16
|
BioCo
|
BioCo
|
BioCo
|
BioCo
|
T0: 42
T1: 44
T2: 45
T3: 46
|
T0: 21
T1: 14
T2: 2.5
T3: 5
|
T0: 6
T1: 6
T2: 5
T3: 5
|
T0: 3
T1: 3
T2: 3
T3: 3
|
T0: 5
T1: 5
T2: 5
T3: 5
|
T0: 3
T1: 3
T2: 3
T3: 3
|
Unilateral IACs
|
14
|
F
|
5
|
11
|
20
|
BioCo
|
BioCo
|
BioCo
|
BioCo
|
T0: 43
T1: 45
T2: 44
T3: 48
|
T0: 13
T1: 9
T2: 9
T3: 12
|
T0: 5
T1: -
T2: 4
T3: 3
|
T0: 3
T1: -
T2: 3
T3: 3
|
T0: 3
T1: 2
T2: 2
T3: -
|
T0: 3
T1: 3
T2: 3
T3: 3
|
Unilateral IACs
|
15
|
F
|
13
|
15
|
20
|
No DMARD
|
|
No DMARD
|
MTX
|
T0: 35
T1: 45
T2: 45
T3: 45
|
T0: 32
T1: -
T2: 8
T3: 3
|
T0: 6
T1: 6
T2: 4
T3: 3
|
T0: 3
T1: 3
T2: 4
T3: 2
|
T0: 3
T1: 3
T2: 3
T3: 3
|
T0: 3
T1: 3
T2: 3
T3: 3
|
Bilateral IACs
|
*Additive and progressive MRI score (36, 37) ** Metylprednisolone acetate; Inj, injection; Medic, medication; MIO, maximal incisal opening; MRI, magnetic resonance imaging; FU, follow-up; MTX, methotrexate; BioCo, biologics alone or in combination with other DMARDs; disease modifying antirheumatic drugs; JIA, juvenile idiopathic arthritis; TMJ, temporomandibular joint; IACs, intraarticular corticosteroid injections; T0=Pre-injection, T1= 2-months follow-up, T2= 1-year follow-up, T3= 2-year follow-up; - missing data
Side effects
In our study no severe side effects occurred in terms of infection, bleeding or intraarticular calcifications, even if a computed tomography (CT) scan may better show calcifications. However, 2 patients had worsening in bone damage at 2-year follow-up. In addition two patients had worsened score for bone damage at 1-year follow-up but have not yet reached 2-year follow-up. However, these patients had all ongoing inflammation and one of them a trauma to the mandible that may explain the damage. Another patient worsened in bone damage between injection and 2-months follow-up but improved at the 2-year follow-up. Furthermore, three patients improved in bone damage from baseline to 2-year follow-up and 1 patient improved at 1-year follow-up.
Other studies have reported short-term adverse effects such as facial swelling, skin atrophy, pain, TMJ stiffness, chewing dysfunction, fever and TMJ calcifications/ossifications (15, 16, 42-44, 51). A chart review by Ringold et al. (51) described heterotopic ossification in the TMJ in children receiving 1–5 TMJ IACs, but the authors were unable to say whether these ossifications were the result of the IACs treatment or due to severe, long-standing TMJ inflammation. Also Lochbuhler et al. (22) reported severe side effects such as ossifications in the TMJs after repeated IACs. Rate of osseous deformities increased from 51% at baseline to 62% at the end of their study, with progression to severe condylar destruction in 26% of joints including 24% with development of intraarticular calcifications / ossifications. Importantly, mandibular growth rate was reduced compared to the normal age- and sex-matched mean growth rate. In that study injections were however performed repeatedly. It is unclear whether the adverse effect of ossifications and reduced mandibular growth is a problem mainly of repeated steroid injections. We could not evaluate the effects on mandibular growth since the patients were mostly fully grown at the time the injection was performed. Our study may point to a single steroid injection as a treatment option for severe symptoms of TMJ-arthritis unresponsive to systemic treatment in skeletally mature individuals.
Study strengths and limitations
A strength of the present study is the prospective study design with standardized examination and MRI protocols in a clinical setting. MRI scoring assessments were performed by two experienced specialists and masked regarding whether the images were pre- or post-treatment. In addition, the clinical examiners used standardized examination protocols and were repeatedly calibrated, even if recalibration not necessary always change the inter-examiner reliability (33). Our study sample is comparable to population-based JIA cohorts and case-control studies regarding gender and JIA category distribution (7, 8, 16). A limitation is that clinical examiners and the patients were not masked before and after treatment, when assessing clinical variables such as MIO and pain. It must be emphasized that the patient group is small, and therefore the statistical analyses of the main clinical and imaging outcomes, and the discrepancies between the two scoring systems must be interpreted with caution. Furthermore, we found considerable intra-observer variability for some domains of the MRI scores, and our interpretation of the scoring systems may differ from that of the original authors.