Juvenile Idiopathic Arthritis (JIA) is arthritis of unknown etiology that begins
before the 16th birthday and persists for at least 6 weeks (Petty
et al., 2004). It is a chronic and heterogenous disease characterized
by prolonged synovial inflammation that may lead to alterations in joint structures.
Permanent changes may also develop in extraarticular organs and systems such
as the eye (as a complication of chronic anterior uveitis) or the kidney (due
to systemic amyloidosis), or may result from side effects of medications (Viola
et al., 2005).
JIA encompasses several disease categories with diverse signs, symptoms and
genetic complexity (Wallace et al., 2004). The
International League of Associations for Rheumatology (ILAR) has revised the
classification of JIA in Edmonton 2001. It included the following categories
: systemic arthritis, oligoarthritis persistent or extended, polyarthritis rheumatoid
factor positive, polyarthritis rheumatoid factor negative, psoriatic arthritis,
enthesitis related arthritis and undifferentiated arthritis (Petty
et al., 2004). All joints can be involved in JIA including the temporomandibular
joint (TMJ). Involvement of the TMJ was first reported in 1897 by Still when
he described chronic arthritis in childhood.
The reported frequency of TMJ affection varied in literature depending on the
population investigated, the subtypes of JIA represented and the method by which
TMJ disease is diagnosed. In all subtypes of JIA, one or both TMJs can be affected
and may even be the initial joint involved (Martini et
S100A12 (Calgranulin C) is a member of the S100 protein family which are acidic
proteins of low molecular mass characterized by cell type specific production
and the prescence of calcium binding domains (Foell et
al., 2007). Human S100A12 is predominantly expressed and secreted by
neutrophil granulocytes. Intracellular S100A12 upon calcium dependent activation
interacts with target proteins to regulate cellular functions. Extracellular
S100A12 shows cytokine like characteristics. It is markedly over expressed in
inflammatory compartments and elevated serum levels of S100A12 were found in
patients suffering from various inflammatory, neurodegenerative and neoplastic
disorders. It's interaction with the multiligand receptor of advanced glycation
(RAGE) and it's soluble form (sRAGE) plays a central pathogenic role. Several
clinical evidences suggest a high potential of S100A12 as a sensitive and specific
diagnostic marker of inflammation. An increase in it's concentrations have been
found in serum of patients with rheumatoid arthritis (Pietzch
and Hoppmann, 2009). Imaging remains an important tool in the assessment
of juvenile arthritis patients. With improved treatment options, imaging must
be very sensitive in detecting both inflammatory and destructive changes. Magnetic
Resonance Imaging (MRI) in particular can detect synovitis and adds significant
information to the clinical examination particularly in TMJ and foot joints
The objective of this study is to measure serum levels of the proinflammatory protein S100A12 secreted by human neutrophils, moreover to find out clinical as well as contrast enhanced MRI findings of TMJ arthritis among JIA patients aiming to know the correlation between each of them and also to different disease parameters as TMJ inflammation may occur without manifestations; it is in need for thorough evaluation and S100A12 may be a future anti-inflammatory treatment in JIA.
MATERIALS AND METHODS
The present study included twenty patients (12 girls and 8 boys) with Juvenile
Idiopathic Arthritis (JIA). Their age at the start of the study ranged from
7.5-17.0 years. Patients had either oligoarticular, polyarticular or systemic-onset
JIA according to the criteria of the International League of Associations for
Rheumatology (ILAR) (Petty et al., 2004). They
were attending the Pediatric immunology, Rheumatology and Rehabilitation outpatient
clinics in Ain Shams University Hospitals. Ten age and sex matched apparently
healthy subjects were enrolled in the study as a control group. This study had
started on 8th of January, 2008 and finalized on 12th of December, 2009.
Patients with cardiac pacemakers, metal implants or dental braces were excluded from the study.
After informed consent was obtained from patients or their legal guardians and the study was approved by Ain Shams Medical Ethics Committee (FMASU REC). All patients were subjected to the following:
Full history taking
Clinical examination: Thorough general and musculoskeletal examination
were done for all patients with special emphasis to skin rash, fever, ocular
affection, hepatosplenomegaly, number and distribution of affected joints.
A clinical activity score was assigned (Tselepis et
al., 1999) based on the presence of joint swelling, warmth, redness,
range of motion, pain, morning stiffness and the use of anti-inflammatory medications.
The score ranged from 0 to 5 with 0 representing no complaints or physical findings
of active disease and no use of anti-inflammatory medications and 5 representing
very active clinical disease and the use of anti-inflammatory medication. The
disease was defined as active if the score was ≥3 and inactive if the score
Functional ability was assessed using Childhood Health Assessment Questionnaire
(C-HAQ): which describes the child's usual activities in 8 domains over the
past week. It includes dressing and grooming, arising, eating, walking, with
or without aids or assistive devices, hygiene, reach, grip and activities. Each
question is scored from 0 to 3, (0 = no difficulty. 1 = some difficulty. 2 =
much difficulty, 3 = unable to do). The score for each of the 8 functional areas
were averaged to calculate the Disability Index. Patients were classified as
mildly disabled (score < 1), moderately disabled (score 1 to 2) or severely
disabled (score > 2) (Singh et al., 1994).
Pain assessment using a visual analogue scale (Mantha et
Clinical assessment of TMJ: Patients were asked about history of TMJ
pain at rest or on movement (e.g., opening or chewing), morning stiffness longer
than 15 min and crepitations. Clinical examination included : detection of joint
tenderness (by palpation on the area infront of ear trigs and external acoustic
meatus (Billiau et al., 2007)), crepitations (by using a stethoscope
while the patient is asked to perform movement of the TMJ) (Billiau et al., 2007). The maximal jaw mobility was assessed by maximal interincisal mouth opening
(MIO): upon maximal mouth opening, a millimeter ruler was used to measure the
vertical distance from the incisal edge of the upper maxillary incisor to the
opposing mandibular incisor adding the vertical overbite. The MIO was considered
to be restricted when ≤40 mm (Agerberg, 1974).
Laboratory investigations: Complete hemogram analysis and differential blood count using coulter JS plus cell counter (Coulter Electronics, FL, USA).
Erythrocyte Sedimentation Rate (ESR) using Westergreen method.
C-Reactive Protein (CRP) quantitative determination (Gmbh,Hannover,Germany).
Rheumatoid Factor (RF) detection (Plasmatec lab. products limited).
Antinuclear antibodies (ANA) by Immunofluorescence assay (Immuno- Diagnostics -USA).
Determination of serum S100A12 concentrations by sandwich enzyme linked immunosorbent assay (ELISA) (Maxisorp; Nunc. Hamburg, Germany) according to manufacturer instructions.
Samples collection: Eight milliliter of venous blood were withdrawn from each patient and subjects of the control group. Two milliliter were added onto EDTA tube for differential blood count and ESR. The remaining 6 mL were allowed to clot for serum separation.
Imaging study of TMJ by MRI: The MRI was carried out using a 1.5 Tesla
Signa Horizon magnet. The examination was performed with a TMJ coil. The MRI
evaluation included coronal T1 and T2 weighted images,
sagittal T1 and T2 weighted images and after injection
of gadolinium-based contrast medium, sagittal and coronal fat saturated T1
weighted images. The variables evaluated were enhancement of the synovial membrane,
condylar morphology, presence of pannus and intraarticular fluid. Enhancement
of the synovial membrane which indicates synovial hyperplasia was defined as
an increase in signal intensity of the synovium comparing the precontrast image
with the post-contrast image. Pannus was defined as an intermediate signal of
intraarticular mass on the precontrast T1 weighted images. Intraarticular
fluid (effusion) was defined as low signal intensity mass within the joint cavity.
The MR variables were scored as follows for each joint: enhancement (0 = no
enhancement, 1 = slight enhancement, 2 = strong enhancement), condylar morphology
(0 = no erosions, 1 = mild erosions, 2 = severe erosions), pannus (0 = no visible
pannus, 1 = small amount of pannus, 2 = large amount of pannus) and intraarticular
fluid (0 = no fluid, 1 = small amount of fluid, 2 = large amount of fluid).
The maximum total MR score could therefore be 8 per joint or 16 per patient
(Küseler et al., 2005). The control group were subjected to MRI
of TMJs without contrast.
Statistical analysis: This was done using SPSS 10 for Windows (Statistical Package for the Social Sciences). Descriptive statistics: mean, standard deviation, minimum, maximum and range of numerical data. Frequency and percentage of non-numerical data. Independent sample Student's t test was used to test the difference between two groups (for continuous variables). Chi square test to compare between groups regarding non numerical variables. Correlation (Pearson correlation coefficient r) assessing strength and direction of the linear relationship between two variables. One way Analysis of Variance (ANOVA) test (F) was used to test difference between more than two means. p<0.05 is considered significant and p<0.001 indicates high significance.
RESULTS AND DISCUSSION
This study was conducted on 20 patients with JIA. 10 apparently healthy subjects with matched age and sex have constituted the control group.
Among patients of this study; 12 were girls (60%) and 8 were boys (40%). Similarly the control group was composed of 6 females (60%) and 4 males (40%).
The mean age of patients in this study was 14.32±2.27 years with a range 7.5-17.0 years. While the control group was 14.50±2.87 years and a range of 9.0-17.0 years. Whereas the mean age of patients at disease onset was 9.27±2.84 years, ranging between 3.5-14.0 years. Disease duration of JIA patients showed a mean of 5.05±2.41 years and a range from 1.0 to 11.0 years.
This study included 3 patients (15%) with systemic onset JIA (quotidian fever, rash, arthritis, hepatosplenomegaly and lymphadenopathy). Three patients (15%) with oligoarticular onset JIA and 14 patients (70%) with polyarticular onset JIA. One female with polyarticular onset JIA showed uveitis, hypertension and amyloidosis.
The mean disease activity score of JIA patients was 3.35±1.08, while Child Health Assessment Questionnaire (C-HAQ) showed a mean of 0.96±0.48. The mean value of visual analogue scale for pain was 1.43±0.59. Whereas the mean number of active joints was 4.25± 1.71.
Antinuclear antibodies (ANA) were detected in 5 JIA patients. Within the polyarticular group; 5 patients were positive for rheumatoid factor and 9 patients showed negative results regarding rheumatoid factor.
The mean level of serum S100A12 among JIA patients was 666.0±391.37 ng mL-1 while in the control group it was 81.5±27.99 ng mL-1.
frequency of clinical symptoms and signs of temporomandibular joint in
juvenile idiopathic arthritis patients
Number, %: Percentage, MIO: Maximal interincisal opening. Tenderness on
palpation and decreased maximal interincisal opening were the most frequent
clinical signs of temporomandibular joint affection
resonance imaging T1 weighted image with contrast. It shows
synovial enhancement of both temporomandibular joints more on left side
in a patient with juvenile idiopathic arthritis
Temporomandibular joint clinical parameters showed that symptoms were present among 8 JIA patients (40%): 3 patients (15%), 2 patients (10%) complained of TMJ pain at rest and crepitations respectively. While pain on jaw movement and morning stiffness >15 min were symptoms in 4 patients (20%) for each of them (Table 1). Moreover, clinical examination revealed signs of TMJ involvement in 12 patients (60%) manifested by tenderness on joint palpation in 5 patients (25%), crepitations on movement in 4 patients (20%) and decreased maximal interincisal opening (MIO) in 5 patients (25%) (Table 1). The mean value of MIO among JIA patients was 43.0±4.93 mm while that of controls was 53.33±1.11 mm. No clinical symptoms or signs of TMJ disease could be detected in the control group.
Contrast enhanced MRI was done for 20 patients (40 TMJs): 16 patients (80%) showed MRI abnormalities while 4 patients had no MRI findings. The mean total score for MRI among JIA patients was 5.05±4.21.
Synovial enhancement (Fig. 1) showed the highest frequency
among findings of contrast enhanced MRI, it was detected in 16 patients (80%),
31 TMJs (77.5%) with a mean score 2.60±1.60 While joint effusion (Fig.
2) was present in 13 patients (65%), 19 TMJs (47.5%) with a mean score 1.40±1.46.
frequency of magnetic resonance imaging findings in juvenile idiopathic
arthritis patients and temporomandibular joints
Temporomandibular joints. No.: Number, %: Percentage. Synovial enhancement
showed the highest frequency among contrast enhanced magnetic resonance
resonance imaging T2 weighted image. It shows effusion of temporomandibular
joint in a patient with juvenile idiopathic arthritis
Whereas pannus and erosions were found in 5 patients (25%) for each but in
9 joints (22.5%), 7 joints (17.5%), respectively with a mean score of pannus
0.60±1.18 and erosions 0.45±0.94 (Table 2).
Among JIA patients; there were 4 patients without clinical signs on TMJ examination
but MRI abnormalities were detected in them. Regarding the control group, no
TMJ abnormalities were found by MRI examination.
Comparison between patients and controls: No significant difference
was found between both groups regarding age. The mean value of MIO was highly
significantly decreased in patients than controls. While the mean serum levels
of S100A12 showed high significant increase among JIA patients compared to controls
(p<0.001) (Table 3).
Comparison between patients regarding disease activity: There was a
significant increase in the mean of C-HAQ, pain score, serum S100A12 concentrations,
effusion score and total MRI score in patients with active disease in comparison
to those who were not in the active stage of disease.
between patient and control groups regarding demographic, clinical and
Maximal interincisal opening, Neut: Neutrophil, Hb: Haemoglobin, ESR:
Erythrocyte sedimentation rate. There were high significant differences
between both groups regarding maximal interincisal opening and serum S100A12
levels. NS: Not significant, HS: Highly significant
between juvenile idiopathic arthritis patients with active disease and
without activity regarding demographic, clinical, laboratory and magnetic
resonance imaging data
Number, C-HAQ: Child health assessment questionnaire, MIO: Maximal interincisal
opening, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein,
S: Significance, Syn.: Synovial, MRI: Magnetic resonance imaging. A significant
increase in serum S100A12 concentrations and total magnetic resonance
imaging score for active juvenile idiopathic arthritis patients compared
to the inactive group. NS: Not significant, S: Significant, HS: Highly
The MIO was significantly decreased in patients with active disease. While
a high significant increase in ESR, CRP levels and enhancement score could be
detected among JIA patients with activity compared to those with inactive disease.
No significant difference was detected between both groups regarding neutrophil
count or haemoglobin level (p>0.05) (Table 4).
Comparison between different subgroups of JIA: Using analysis of variance
test; there was significant increase in the mean of disease activity score,
pain score, ESR, CRP levels, serum S100A12 concentrations (Fig.
3) in patients with systemic onset followed by polyarticular onset then
between 3 subtypes of juvenile idiopathic arthritis. There is significant
increase in serum levels of S100A12 in systemic and polyarticular types
compared to oligoarticular type
between 3 subtypes of juvenile idiopathic arthritis. There is high significant
increase in total magnetic resonance imaging score in systemic and polyarticular
types compared to oligoarticular type
While the mean MIO was significantly decreased among systemic JIA group in
comparison to other subtypes. Moreover, total MRI score showed the highest significant
increase among systemic JIA patients then polyarticular type while the lowest
score was detected within oligoarticular group (Fig. 4). No
significant difference could be found between the 3 subtypes regarding neutrophil
count or haemoglobin level (p>0.05) (Table 5).
Comparison between polyarticular RF+ve and RF-ve JIA patients: No significant
differences could be detected between both groups regarding age (t = 1.4, p>0.05),
disease duration (t = 1.2, p>0.05), disease activity score (t = 0.07, p>0.05),
MIO (t = 0.09, p>0.05), serum S100A12 levels (t = 0.62, p>0.05) and total
MRI score (t = 0.81, p>0.05). Polyarticular RF+ve patients were significantly
older at disease onset than RF-ve JIA patients (t = 3.1, p<0.05).
between systemic, polyarticular, oligoarticular juvenile idiopathic arthritis
subtypes regarding demographic, clinical, laboratory and magnetic resonance
Oligoarticular, JIA: Juvenile idiopathic arthritis, Dis: Disease, ons:
Onset, No: Number, Jts: Joints,C-HAQ: Child health assessment questionnaire,
MIO: Maximal interincisal opening, ESR: Erythrocyte sedimentation rate,
CRP: C-reactive protein, S: Serum, Syn. enhan: Synovial enhancement, MRI:
Magnetic resonance imaging. A significant increase in serum S100A12 levels
and total magnetic resonance imaging score in systemic and polyarticular
subtypes compared to oligoarticular patients with juvenile idiopathic
arthritis. NS: Not significant, S: Significant, HS: Highly significant
between juvenile idiopathic arthritis patients with and without magnetic
resonance imaging findings regarding demographic, clinical and laboratory
Magnetic resonance imaging, +ve: Positive, ve: Negative, No: Number,
C-HAQ: Child health assessment questionnaire, MIO: Maximal interincisal
opening, A significant decrease in maximal interincisal opening and a
significant increase in serum S100A12 levels among juvenile idiopathic
arthritis patients with magnetic resonance imaging abnormalities in temporomandibular
joints compared to those without magnetic resonance imaging findings.
NS: Not significant, S: Significant, HS: Highly significant
While the frequencies of TMJ involvement were 80 and 88.9% among polyarticular
RF+ve and RF-ve patients, respectively.
Comparison between JIA patients with and without MRI findings: MRI abnormalities of TMJ have been detected in 16 JIA patients while 4 patients showed no MRI TMJ findings.
There was a significant increase in mean disease activity score, C-HAQ, ESR,
CRP levels and serum S100A12 concentration, meanwhile; MIO showed a significant
decrease among JIA patients with MRI findings when compared to those without
MRI TMJ abnormalities. No significant difference between both groups was found
regarding haemoglobin level or neutrophil count (p> 0.05) (Table
Comparison between JIA patient with or without TMJ pain regarding MIO: A significant decrease in MIO has been detected among JIA patients with pain of TMJ at rest or on jaw movement (t = 2.6, p<0.05, t = 3.6, p<0.05), respectively when compared with patients who didn't complain of TMJ pain.
Association and correlation studies: Using Chi-square test: A significant association has been found between clinical signs of TMJ affection and contrast enhanced MRI TMJ abnormalities (12 patients have shown signs of TMJ affection by both clinical and contrast enhanced MRI examinations (χ2 = 7.5, p<0.05), while this association was not detected regarding symptoms (χ2 = 3.3, p>0.05) among JIA patients.
Serum levels of S100A12 showed a high significant positive correlation with disease activity score, pain score, ESR, CRP serum levels, synovial enhancement score (Fig. 5) and total MRI score (Table 7). No significant correlation was found between serum levels of S100A12 and neutrophil count in JIA patients (r = 0.03, p>0.05) (Fig. 6). A high significant positive correlation could be detected between total MRI score and disease activity score, C-HAQ, pain score by VAS, ESR, serum S100A12 concentrations and CRP levels. While MIO showed high significant negative correlations with disease activity score, C-HAQ, ESR, CRP levels, serum S100A12 concentration and total MRI score (Table 7).
between serum S100A12 levels, magnetic resonance imaging parameters, maximal
interincisal opening and different clinical, laboratory, magnetic resonance
Disease activity, C-HAQ: Child health assessment questionnaire, MIO: Maximal
interincisal opening, ESR: Erythrocyte sedimentation rate, CRP: C-reactive
protein, s.: score, MRI: magnetic resonance imaging, Syn.enh: synovial
enhancement. A high significant positive correlation between serum S100A12
levels and total magnetic resonance imaging score. NS: Not significant,
S: Significant, HS: Highly significant
correlation coefficient test. A high significant positive correlation
between serum S100A12 levels and total synovial enhancement score in patients
with juvenile idiopathic arthritis
Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases
of childhood. Diagnosis is based on clinical observation of persistent arthritis
in one or more joints for a minimum of six weeks, with onset prior to the age
of sixteen years (Sawyer et al., 2005).
Lotze and Tracey (2005) reported that a novel group
of important inflammatory molecules has been introduced to the concept of innate
immunity. In parallel to Pathogen Associated Molecular Pattern (PAMP) as exogenous
factors initiating inflammation. The term Damage Associated Molecular Pattern
(DAMP) proteins for endogenous molecules that exhibit a double life as intracellular
molecules which have a role in cell homeostasis e.g. calcium binding proteins
or chromatin stabilizing molecules but after release into extracellular compartment
as a result of cell damage or inflammation, they become danger signals that
activate immune cells and vascular endothelium.
correlation coefficient test. No significant correlation between serum
S100A12 levels and neutrophil count in patients with juvenile idiopathic
Examples are heat shock proteins, uric acid and S100 proteins (Van
Eden et al., 2005).
S100 A12 (calgranulin C) is a member of S100 family which are calcium binding
proteins and has been described to define a novel pro-inflammatory axis by binding
to the multiligand receptor for advanced glycation end products (RAGE). The
S100A12 is expressed and secreted by activated neutrophilic granulocytes (Foell
et al., 2003). Interaction of S100A12 with RAGE activates endothelial
cells, macrophages and lymphocytes, while blocking of RAGE in experimental models
of arthritis leads to suppression of inflammatory response (Kim
et al., 2005).
Grom and Hirsch (2000) revealed that S100A12 protein
is released from neutrophils during interactions with activated endothelium.
This study showed that serum S100A12 levels were highly significantly elevated
in JIA patients compared to controls which were the same findings obtained by
Foell et al. (2004). Similarly, Sunahori
et al. (2006) detected high serum concentrations of S100A12 in patients
with rheumatoid arthritis.
Wittkowski et al. (2008) reported that S100A12
is a useful marker protein for monitoring disease activity in several inflammatory
diseases. Foell et al. (2004) detected that serum
S100A12 levels were clearly elevated during active disease and that JIA patients
without active inflammation had significantly lower S100A12 serum concentrations
than did patients with active disease. This study is supported by them as serum
levels of S100A12 were significantly elevated in patients with active disease
compared to those without active JIA and a high significant positive correlation
was found between serum levels of S100A12 and disease activity score among patients
De Seny et al. (2008) found that serum concentrations
of S100A12 were significantly correlated with variables that reflect disease
activity of rheumatoid arthritis such as levels of CRP. The results of this
study are in accordance with their study as serum levels of S100A12 showed high
significant positive correlation with CRP levels for patients with JIA.
Foell et al. (2004) recorded that mean serum
levels of S100A12 were significantly the highest among patients with systemic
onset JIA followed by polyarticular then oligoarticular JIA. Yilmaz
et al. (2001) concluded that systemic onset JIA is an aggressive disease
with extensive activation of the immune system influenced by imbalance between
proinflammatory cytokines and immune deactivators. This study is ongoing with
them as serum levels of S100A12 were found to be significantly elevated among
patients with systemic JIA then polyarticular followed by oligoarticular JIA.
Frosch and Roth (2008) reported that the predominant
role of the immune system in systemic JIA is underscored by the high expression
and increased serum concentration of S100A12.
Foell and Roth (2004) noted that S100A12 is secreted
during activation of neutrophilic granulocytes. The present study found no significant
correlation between neutrophil count and serum levels of S100A12. Foell
et al. (2004) suggested that high serum concentrations of S100A12 are
not attributable to elevated numbers of circulating neutrophils as demonstrated
by the lack of correlation to blood neutrophil count. Therefore, it may indicate
the release of S100A12 by extra ordinarily activated neutrophils in systemic
JIA. Jarvis et al. (2006) supported the hypothesis
that there is fundamental activation abnormality of neutrophils in patients
with polyarticular JIA.
Arthritis of TMJ in patients with JIA was recognized as early as 1897 (Ronchezel
et al., 1995) but until recently it has been relatively ignored.
Arthritis of TMJ is a concern, particularly in patients who are growing, because
the mandibular growth plate is located below the fibrocartilage and therefore,
is susceptible to damage from inflammation (Weiss et
The diagnosis of TMJ arthritis has increasingly been based on evidence obtained
by imaging. Orthropantogram, ultrasonography and magnetic resonance imaging
have all been used in evaluation and detection of TMJ arthritis (Jank
et al., 2007).
Küseler et al. (2005) suggested that TMJ
involvement may occur in many JIA cases with activity continuing for many years
without presenting symptoms or clinical signs causing a delay in detection as
they have found in their study that TMJ symptoms and signs were present in 8
and 13 patients with JIA, respectively. This study is supported by them as symptoms
and signs of TMJ disease were detected among 8 and 12 patients, respectively.
On the other hand, Müller et al. (2009)
reported that signs of TMJ affection were detected in 73.3% of JIA patients.
Their high percentage for signs than this study (60% of JIA patients) may be
due that more patients had participated in their study.
Martini et al. (2001) demonstrated that clinical
manifestations such as pain at rest, local morning stiffness, decreased mouth
opening, pain during joint movement may point at TMJ involvement among patients
Twilt et al. (2004) found that clinical symptoms
were not reliable in detection of TMJ involvement in patients with JIA because
they were not present in majority of cases as only 12% of children had complained
of TMJ pain. In this study, TMJ pain at rest could be detected in 15% of patients
This study showed that tenderness on palpation of TMJ and crepitations were
present in 25 and 20% of cases, respectively. A finding which is supported by
Jank et al. (2007), who reported a frequency
of 22.9% for JIA patients with tenderness on TMJ palpation.
Among JIA patients in this study; 4 patients (20%) complained of pain on TMJ
function while Argyropoulou et al. (2009) reported
this symptom in only 2 JIA patients. On the other hand, Engström
et al. (2007) in his follow up study found that the frequency of
pain on TMJ movement had increased to reach 29% of JIA cases. This may be due
to that their patients had longer disease duration. Twilt
et al. (2007) suggested that long disease duration is a risk factor
for TMJ involvement.
Müller et al. (2009) revealed that 23.3%
of their JIA patients had limited Maximal Interincisal Opening (MIO) which supports
our results as the decrease in MIO could be detected in 25% of JIA patients
in this study.
Pedersen et al. (2008) found in their study
that maximal opening capacity of patients were at the lower range of normal
but it was significantly decreased in JIA patients compared to controls. Our
findings are consistent with them as the mean maximal opening capacity was highly
significantly lower in patients with JIA compared to controls. It was also significantly
lower among patients with systemic JIA than the polyarticular type and it was
the highest among patients with oligoarticular disease. A finding which was
confirmed by Arabshahi et al. (2005) as they
have found that MIO was better among oligoarticular JIA patients than polyarticular
Billiau et al. (2007) revealed that restricted
MIO was the most frequent clinical finding occurring in nearly one third of
patients 33.3% and it was more frequent among JIA patients with long standing
and active disease, they suggested that impaired function of the TMJ and surrounding
muscles during activity explains the association with disease activity and possibly
with severity. This study is ongoing with them as decreased MIO was one of the
most frequent signs of TMJ involvement in patients with JIA (25% of cases) and
it was significantly decreased for patients with active disease compared to
those with no activity. Reduced MIO also showed high significant negative correlations
with disease activity score and child health assessment questionnaire.
In the present study; JIA patients with TMJ pain showed a significant decrease
of the mean MIO in comparison to patients without pain. Moreover, there was
a significant negative correlation between reduced MIO and pain score. Arabshahi
et al. (2005) agreed with this study, they have found that the mean
MIO was lower in patients with TMJ pain than those without pain, they reported
that this reflects pain limited movement.
The lack of symptoms and abnormalities on TMJ examination does not exclude
the presence of TMJ disease, so radiological examination on regular basis is
necessary (Twilt et al., 2003; Weiss
et al., 2008). The MRI is considered the gold standard for the study
of TMJ disease because it evaluates bone and depicts intraarticular fluid. Contrast
enhanced MRI after injection of gadolinium demonstrates an inflammatory state
in the joint (Pedersen et al., 2008; Argyropoulou
et al., 2009).
In this study 80% of JIA cases showed TMJ affection using post-contrast MRI.
Weiss et al. (2008) supported our results as
they have recorded a frequency (75%) of TMJ arthritis using gadolinium enhanced
MRI among their patients. They revealed that it is at the higher end of previously
reported ranges 17-87% (Pedersen et al., 2001;
Twilt et al., 2006) which indicates that TMJ
is one of the most commonly involved joints in patients with JIA. While Twilt
et al. (2004) detected TMJ abnormalities among 45% of patients with
JIA diagnosed by orthopantogram. They said that the frequency of TMJ involvement
depends on the radiographic tool used to find out TMJ disease. Küseler
et al. (2005) suggested that contrast enhanced MRI may be an efficient
method in diagnosing inflammatory changes in TMJ.
Küseler et al. (2005) reported that patients
in their study were diagnosed to have JIA due to arthritis in joints other than
the TMJ and they were surprised to see that the majority already had signs of
TMJ involvement on MRI examinations. They detected synovial enhancement in 93%,
erosions in 71% and pannus in 26% of TMJs. This study is ongoing with them regarding
the high frequency of temporomandibular joints with synovial enhancement (75.5%)
but it detected lower frequency of erosions (17.5%) and pannus (22.5% ).
This study has detected effusion in 47.5% of TMJs among patients with JIA.
On the contrary Arabshahi et al. (2005) showed
a frequency of 57% for TMJ effusion using MRI. This may be due to that their
patients were younger at disease onset than JIA patients in this study. Arabshahi
and Cron (2006) suggested that younger age at disease onset is one of the
causes of bad prognosis regarding TMJ. On the other hand, Argyropoulou
et al. (2009) found that by MRI, effusion was present in only 10% of
TMJs. While Küseler et al. (2005) supported
this study as TMJ effusion was detected in 13 JIA patients in their and our
Pedersen et al. (2001) suggested that TMJ abnormalities
as detected by MRI are dependent on disease duration. The results of this study
revealed that patients with TMJ MRI findings have longer disease duration than
those without TMJ MRI signs although, the difference hasn t reached statistical
Twilt et al. (2007) concluded that JIA disease
activity and severity could be reflected in TMJ involvement. In addition, Twilt
et al. (2008) reported that inactive disease state prevents TMJ abnormalities
among patients with JIA and this needs institution of more aggressive therapy
that will decrease disease activity. Argyropoulou et
al. (2009) detected a significant association between abnormal MRI findings
of TMJs and disease activity among patients with JIA. The present study is in
accordance with them as we have found a high significant increase in mean of
synovial enhancement score and a significantly higher effusion, total MRI scores
in JIA patients with active disease compared to those who were not in the active
phase of the disease and our results have also showed a high significant positive
correlation between total synovial enhancement, effusion and MRI scores with
both disease activity, C-HAQ scores. On the contrary, Billiau
et al. (2007) found no correlation between disease characteristics such
as disease activity, disease duration on one hand and radiological manifestations
of TMJ abnormalities in patients with JIA. This difference with our results
may be due to that they have examined TMJs by orthopantogram while contrast
enhanced MRI was the tool used to diagnose TMJ disease in this study.
Despite increased TMJ changes by MRI, little symptoms could be detected (Pedersen
et al., 2008) they suggested that symptoms under estimate the inflammatory
state of TMJ among patients with JIA. On the other hand, Argyropoulou
et al. (2009) reported that all patients with clinical signs on TMJ
examination had TMJ disease on post contrast MRI assessment. This study is ongoing
with them as we have detected a significant association between MRI findings
and clinical signs of TMJ involvement while this association was not significant
regarding symptoms. Küseler et al. (2005)
proposed that clinical examination seems to be more reliable than asking for
symptoms of TMJ affection, since, all patients showing findings by clinical
examination also had pathological signs on post contrast MRI. So, it seems more
reasonable to select patients without clinical findings for MRI examination.
Our results are supported by Küseler et al. (2005)
as this study have included 4 JIA patients without clinical signs of TMJ involvement
but post contrast MRI studies showed TMJs abnormalities.
Pedersen et al. (2001) reported that the severity
of TMJ involvement was more pronounced in systemic and polyarticular JIA. Arabshahi
and Cron (2006) also noted that the worst out come for TMJ affection was
detected in patients with systemic or polyarticular disease. The results of
this study are ongoing with them as the total MRI score of TMJ abnormalities
was significantly higher among patients with systemic followed by polyarticular
then oligoarticular JIA. This may be explained by Wallace
et al. (2005) opinion that patients with oligoarticular arthritis are
more likely to have longer periods of inactive disease compared to the polyarticular
type. Our results are supported by their opinion as disease activity score was
significantly higher for children with systemic followed by polyarticular JIA
while those with oligoarticular type showed inactive disease.
In this study, polyarticular RF positive patients showed a lower frequency
of TMJ involvement 80% than the RF negative cases 88.9%. Twilt
et al. (2004) in their study noted that, it is surprising that the
frequency of TMJ arthritis within the polyarticular RF positive group which
is known by it's erosive character had a low frequency of TMJ affection. They
said that this may be due to that RF positive patients had late disease onset
compared by others. They postulated that older age at disease onset may be associated
with less manifestations.
Taylor et al. (1993) revealed that the mechanism
of TMJ involvement in JIA is unknown but it is probably related to the presence
of synovial inflammation. Martini et al. (2001)
proposed that proinflammatory cytokines can cause abnormalities of TMJs in JIA.
In addition, Twilt et al. (2004) suggested that
the severity of TMJ involvement is directly related to inflammatory variables
of JIA. S100A12 has been known to be involved in the process of communication
between neutrophils and endothelium thus triggering adhesion and invasion of
inflammatory cells. Thus, neutrophils represent an important cellular component
that contributes to synovial inflammation (Wipke and Allen,
2001). This study is supported by them as we have found a high significant
positive correlation between MRI total score of TMJs and serum S100 A12 (the
proinflammatory protein) as well as CRP levels among JIA patients.
Küseler et al. (2005) reported that studies
correlating changes of MRI results in joints other than the TMJ with histological
findings have shown that enhancement of synovial membrane on using gadolinium
enhanced MRI is related to synoival inflammation (Gaffney
et al., 1995). Animal studies of TMJ arthritis comparing histological
findings with MRI support this conclusion. Data from murine models of arthritis
demonstrated the ability of S100A12 to trigger synovial inflammation, in addition;
blocking the interaction of S100A12 with its receptor RAGE has suppressed clinical
and histological evidence of arthritis in mouse models (Schmidt
et al., 2001). This may explain the high significant positive correlation
between total score of synovial enhancement on one hand and serum S100 A12 concentrations,
CRP levels on the other hand, among JIA patients in this study. Müller
et al. (2009) noted that the presence of synovial enhancement is
an indicator of inflammation.
Küseler et al. (2005) recorded that contrast
enhanced MRI is a helpful tool in detecting TMJ abnormalities. Pedersen
et al. (2008) recommended clinical examination of children with JIA
every 6 months. Once TMJ arthritis is discovered, the primary goal is to control
synovitis by medications. Foell et al. (2004)
suggested a functional role of S100A12 in JIA. Schmidt et
al. (2001) reported that anti S100A12 antibodies revealed anti-inflammatory
effects in mouse models of arthritis. Twilt et al.
(2004) noted that in conjunction with medical treatment, the basic principles
in rheumatology such as: heat, cold therapy and exercises are needed to improve
TMJ range of motion. Weiss et al. (2008) asked
an important question, should a child with arthritis of 2 temporomandibular
joints and 3 other joints with active disease be classified as polyarticular
TMJ arthritis could be detected in most cases of JIA using contrast enhanced MRI. The S100A12 may reflect neutrophil activation during synovial inflammation by the increase in it's serum levels in JIA patients. It may also point to synovial inflammation thorough it's significant correlations with synovial enhancement, effusion, total MRI and disease activity scores. Systemic and polyarticular JIA subtypes showed the worst results regarding S100A12 serum levels and MRI scores. Contrast enhanced MRI may be recommended in JIA patients especially those with no clinical signs of TMJ disease. Further studies on larger scale of JIA patients are needed for monitoring TMJ arthritis and for investigating the role of S100A12 in human arthritis as it may lead to a potential therapy that focuses on the pro-inflammatory activities of human S100A12.