The Temporomandibular Joint in Juvenile Idiopathic Arthritis : Psychosocial, clinical, imaging and parotid saliva biomarkers

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The disease can affect the temporomandibular joint (TMJ) and cause orofacial growth disturbances, pain, and jaw dysfunction. TMJ arthritis is often asymptomatic and therefore a challenging joint to diagnose. Clinical assessment of the TMJ is hampered by the low sensitivity and specificity of joint pain and the absence of physical findings early in the disease process. More specific methods are therefore needed for diagnosing TMJ arthritis. Saliva and blood are promising as diagnostic fluids for various diseases. Also, adolescents with chronic pain report high rates of psychosocial stress. Psychosocial stress may also be involved in JIA as a trigger and maintaining factor of the disease. Aim: The main aim of this thesis research was to investigate the relation between clinical variables, psychosocial factors, MRI findings, and inflammatory biomarkers in saliva and blood in relation to TMJ involvement in JIA. The secondary aim was to investigate the relation between stress and change in stress over time in comparison with orofacial pain, psychosocial factors, and jaw function in JIA patients. Methods: This was a cross-sectional case-control study and a longitudinal cohort study. Forty-five patients (6-16 years old) with JIA and 16 healthy age- and sex-matched healthy individuals were examined according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The study subjects completed questionnaires regarding psychosocial factors and underwent bilateral MRI of their TMJs. Unstimulated parotid saliva and venous blood samples were collected. Biochemical analyses were performed using a multiplex platform electrochemiluminescence assay from Meso Scale Discovery (MSD) for measuring cytokine concentrations in saliva and blood. A two-year prospective follow-up study was performed in 40 JIA patients from our original baseline study. The JIA patients underwent the same clinical examination and completed the same questionnaires regarding psychosocial factors as in the baseline studies. Results: The JIA patients with orofacial pain had higher degrees of stress, depression, catastrophizing, and jaw dysfunction than did those JIA patients without such pain. These factors were also associated with orofacial pain intensity. Additionally, patients with orofacial pain had higher systemic inflammatory activity. In the two-year follow-up study, we observed that change in stress was associated with changes in catastrophizing, psychological distress, as well as limitations in both general and jaw functions. Regarding TMJ MRI findings, there were no significant differences between JIA patients and healthy individuals in either the inflammatory or damage domain. Moderate/severe TMJ changes in the inflammatory and damage domains were, however, only found in the JIA patients. Among JIA patients, orofacial pain intensity was correlated to TMJ bone marrow edema, and pain in jaw muscles during jaw function was related to both TMJ bone marrow edema and erosion. JIA patients had lower concentrations of interleukin receptor 6 (IL-6R) and glycoprotein 130 (gp130) in parotid saliva than in plasma. Higher concentrations of IL-6 were found in parotid saliva than in plasma. The members of the interleukin-6 family (i.e., IL-6, IL-6R, and gp130) in parotid saliva were found to be explanatory factors for the presence of bone marrow edema and effusion in the JIA patients. Conclusions: Orofacial pain in patients with JIA is associated with stress, psychological distress, jaw dysfunction, and loss of daily living activities. Pain intensity seems to be the major aspect related to these factors. Increased disease activity with more joint involvement seems to be an important factor contributing to orofacial pain in JIA. Myalgia, in addition to arthritis, seems to be an important source of orofacial pain in these patients. Maintaining a low stress level in JIA patients seems to be crucial, as an increase in stress level over a two-year period appears to negatively impact both jaw function as well as psychosocial distress and catastrophizing. There was an overlap of TMJ MRI findings regarding signs of inflammatory and bone tissue changes between JIA patients and healthy individuals. Among, JIA patients, the presence of inflammatory MRI signs, and bone marrow edema seems to worsen orofacial pain intensity. The IL-6 family in parotid saliva is associated with TMJ bone marrow edema and effusion in patients with JIA, suggesting that IL-6 has promising properties as a parotid saliva biomarker of TMJ inflammatory activity. In addition there seems to be local production of the IL-6 family in the parotid gland in JIA patients and healthy individuals. However, parotid saliva does not seem to reflect the plasma content in terms of the investigated biomarkers in JIA.Juvenil idiopatisk artrit (JIA) är ett samlingsbegrepp för kroniska ledinflammatoriska sjukdomar hos barn. I Sverige insjuknar årligen ungefär 200 barn. För att få diagnosen JIA skall debuten ske före 16 års ålder. Vid JIA kan de flesta leder drabbas med olika problem som följd. Den här avhandlingen fokuserar på käkleden där inflammation (käkledsartrit) på grund av JIA kan orsaka smärta, brosk- och bennedbrytning och nedsatt käkfunktion. Inflammationen kan även påverka tillväxt så att patienterna kan få en liten haka och öppet bett. Samtidigt är det så att många barn med JIA i käkleden inte upplever några symtom, trots en pågående käkledsinflammation. Detta gör det mycket svårt att upptäcka sjukdomen i käkleden tidigt. Idag saknas etablerade och validerade kliniska diagnostiska kriterier för att identifiera patienter med käkledsartrit. Det betyder att metodik för att undersöka patienter och definition av käkledsartrit vid JIA varierar avsevärt, både i det kliniska arbetet och i vetenskapliga studier samt mellan olika kliniker och länder. Syftet med denna avhandling var att undersöka hur smärta och funktion i käksystemet relaterar till generell inflammatorisk aktivitet, biomarkörer i parotissaliv och blod, inflammatoriska förändringar i käkled och psykosociala faktorer, både vid första undersökningen och över en två-årsperiod. Avhandlingen visar bland annat att smärta i käksystemet har tydliga samband med stress och nedsatt käkfunktion där smärtintensiteten verkar vara den viktigaste faktorn. Ökad stress över en två-årsperiod är associerad med försämrad käkfunktion och mående. Det finns ett överlapp av fynd på magnetkamera vad gäller käkledsförändringar mellan patienter med JIA och friska kontroller. Hos patienterna med JIA förefaller benmärgsöden i käkledshuvudet vara relaterat till smärta i käksystemet. När det gäller de inflammationssubstanser vi undersökte i saliv visar denna avhandling att Interleukin-6-familjen möjligen kan ha egenskaper som biomarkör relaterat till benmärgsödem i käkledshuvudet. Sjukdomen JIA är en klinisk utmaning att identifiera, diagnostisera, följa och behandla vad gäller käkleden. Här behövs mycket mer forskning där ett viktigt steg är att etablera valida diagnostiska kriterier. De drabbade barnen kan idag få stora skador i käkleden, ibland med associerad smärta och nedsatt käkfunktion. Sammanfattningsvis visar avhandlingen att stress samt smärta och käkfunktion i hela käksystemet är viktiga faktorer att undersöka och ta med i den kliniska bedömningen och behandlingen. Det överlapp av fynd från käkleden vid undersökning med magnetkamera mellan barn med JIA och friska kontrollen innebär att man behöver tolka fynd från magnetkamera med försiktighet.Paper III is not included in the fulltext onlinePaper III in dissertation as manuscript</p

Periodontal Health in Children with Juvenile idiopathic arthritis

AIM: To investigate gingival inflammation and prevalence of four specific periodontal associated pathogens in Juvenile idiopathic arthritis (JIA) in relation to orofacial pain, jaw function and systemic inflammatory activity in JIA. METHODS: Forty-five children with JIA and 16 healthy children as controls, were enrolled. Subjects were examined and classified according to the diagnostic criteria for temporomandibular disorders (DC/TMD). Pain, pain-related disability and jaw function were also assessed. A clinical periodontal examination was performed. Subgingival plaque samples were collected and analyzed for semiquantitative levels of the following periodontal pathogens; Aggregatibacter actinomycetemcomintans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. RESULTS: No significant difference between JIA and healthy individuals was observed regarding the clinical periodontal variables plaque, gingivitis, probing pocket depth or the investigated periodontal pathogens. P. gingivalis and T. forsythia were detected in both groups. In the group with JIA, no significant correlation was found between orofacial pain, jaw function, systemic inflammatory activity and periodontal disease, including levels of P. gingivalis and T. forsythia.  CONCLUSION: This study suggests that the periodontal disease-associated bacteria P. gingivalis and T. forsythia do not contribute to neither periodontal disease, systemic inflammatory activity nor orofacial pain and jaw dysfunction, including TMJ arthritis, in JIA patients in Sweden

Unstimulated Parotid Saliva Sampling in Juvenile Idiopathic Arthritis and Healthy Controls : A Proof-of-Concept Study on Biomarkers

The aims of this proof-of-concept study were to develop a collecting method for unstimulated parotid saliva in juvenile idiopathic arthritis (JIA) patients and healthy children and to investigate if inflammatory biomarkers could be detected in these samples. Forty-five children with JIA (median age of 12 years and 25th-75th percentile of 10-15 years; 33 girls and 12 boys) and 16 healthy children as controls (median age of 13 years and 25-75th percentile of 10-13 years; 11 girls and 5 boys) were enrolled in this study. Unstimulated parotid saliva was collected with a modified Carlson-Crittenden collector. The salivary flow rate and salivary concentrations of total protein and inflammatory mediators were assessed. The Meso Scale Discovery electrochemiluminescence immunoassay was used for analyzing protein concentrations and the inflammatory biomarkers. Sufficient parotid saliva volumes to be analyzed could be collected with the collection device. JIA patients had a lower sampling saliva volume (p = 0.008) and saliva flow rate (p = 0.039) than controls. The total protein concentrations and inflammatory biomarkers were measured in the last six healthy subjects. The median protein concentration was 1312 mu g/mL (25th percentile: 844 mu g/mL and 75th percentile: 2062 mu g/mL; n = 6) and quantifiable concentrations of 39 inflammatory proteins could be assessed in these samples. In conclusion, this study indicates that the saliva sampling method, as used in the present study, is able to collect sufficient sample volumes in children, and that it is possible to analyze various inflammatory biomarkers in the collected saliva

Increase in stress contributes to impaired jaw function in juvenile idiopathic arthritis : a two-year prospective study

BackgroundStress in patients with Juvenile Idiopathic Arthritis (JIA) has been found to be associated with orofacial pain, psychological distress, jaw dysfunction and loss of daily activities in a cross-sectional study. The aim of this study was to investigate the relations between stress and change of stress over time versus changes in orofacial pain, psychosocial factors and jaw function over a two-year period in patients with JIA.MethodsThis is a two-year prospective follow-up study involving 40 JIA patients. At baseline (2015) the median age was 12 years and at two-year follow up (2018) 14 years. The JIA patients were examined clinically and with questionnaires at baseline and follow-up with the diagnostic criteria for temporomandibular disorders (DC/TMD) and completed the same set of DC/TMD questionnaires regarding orofacial pain symptoms and psychosocial factors.ResultsChange in stress was associated with change in catastrophizing, psychological distress as well as limitation in general function and jaw function.ConclusionsThis study emphasizes the importance of maintaining a low stress level in patients with JIA since an increase in stress level over a two-year period seems to impair jaw function as well as psychological distress and catastrophizing

Orofacial pain in juvenile idiopathic arthritis is associated with stress as well as psychosocial and functional limitations

Background The aim of this study was to investigate relations between psychosocial factors, signs and symptoms of orofacial pain and jaw dysfunction in patients with juvenile idiopathic arthritis (JIA). Methods Forty-five patients with JIA (median age 12 years) and 16 healthy matched controls (median age 13 years) were examined according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The subjects answered the DC/TMD questionnaires regarding psychosocial factors (pain intensity, pain–related disability, depression, stress, catastrophizing, pain locations and jaw function). Results JIA patients with orofacial pain had higher degree of stress, depression, catastrophizing and jaw dysfunction compared to subjects without. In turn, these factors were associated with orofacial pain intensity. Also, patients with orofacial pain had higher systemic inflammatory activity. Conclusions Orofacial pain in patients with JIA is associated with stress, psychological distress, jaw dysfunction and loss of daily living activities. Pain intensity seems to be the major pain aspect related to these factors. In addition, systemic inflammatory activity appears to be an important factor contributing to orofacial pain in JIA.Funding Agencies|Research Council in Southeast Sweden; Public dental health Scientific Funds in Ostergotland; County (Ostergotland County Council) Sweden; Swedish Dental-Societys Scientific Funds; American Dental Society of Sweden; Malmo University</p

Juvenile idiopathic arthritis and the temporomandibular joint : a case-control study of magnetic resonance imaging findings in relation to clinical and psychosocial factors.

AIM: In juvenile idiopathic arthritis (JIA), the temporomandibular joint (TMJ) is a particularly challenging joint to assess both clinically and with imaging. The aim of this article is to investigate TMJ magnetic resonance imaging (MRI) findings in relation to clinical and psychosocial factors in patients with JIA and healthy individuals related to TMJ arthritis in JIA. MATERIALS: In total, 45 patients (6-16 years) with JIA and 16 healthy age- and sex-matched controls were examined according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The subjects answered questionnaires about psychosocial factors (pain intensity, pain-related disability, depression, stress, catastrophising, pain locations, and jaw function) and underwent bilateral MRI of the TMJ. RESULTS: There were no significant differences between JIA patients and healthy individuals in any of the TMJ MRI findings. Moderate/severe changes among JIA patients were found only for effusion, synovial thickening, condylar flattening, and erosion, with no moderate/severe changes in healthy individuals. In JIA patients, orofacial pain intensity was related to TMJ bone marrow oedema, and pain in jaw muscles during jaw function was related to TMJ bone marrow oedema and erosion. There were no significant correlations between psychosocial aspects and MRI findings. CONCLUSION: This study indicates a substantial overlap of TMJ MRI findings in both the inflammatory domain and the damage domain between JIA patients and healthy individuals. In JIA patients, the inflammatory MRI sign of bone marrow oedema seems to influence orofacial pain intensity